Tissue repair and sealing devices having a detachable graft and clasp assembly and methods for the use thereof

ABSTRACT

Provided are tissue repair and sealing devices, and methods for the use of tissue repair and sealing devices, for use in both minimally invasive surgical (MIS) procedures and open, non-MIS procedures to rapidly repair tissue fenestrations and create a pressure-resistant, watertight seal in a tissue barrier. Tissue repair and sealing devices disclosed herein comprise an integrated graft and deployable clasp assembly and an applicator assembly having a clasp retain and release member that is slidably connected to a folded, deployable clasp. The applicator assembly places a graft on a tissue inner surface and a deployable clasp on a tissue outer surface to secure the graft to the tissue inner surface to, thereby, repair a tissue fenestration and create a watertight barrier.

CROSS-REFERENCE TO RELATED APPLICATIONS

This U.S. non-provisional patent application was filed on Jan. 22, 2021as U.S. patent application Ser. No. 17/156,162 and claims the benefit ofU.S. Provisional patent Application No. 62/965,722, which was filed onJan. 24, 2020. The contents of U.S. Provisional Patent Application No.62/965,722 are incorporated herein by reference in their entirety.

BACKGROUND OF THE DISCLOSURE Technical Field

The present disclosure relates, generally, to the field of medicine, inparticular to surgery and surgical procedures, including both minimallyinvasive surgical (MIS) procedures and open surgical (non-MIS)procedures. Disclosed herein are tissue repair and sealing devices, andmethods for their use, which comprise a detachable graft and claspassembly for repairing tissue fenestrations, such as those that occurduring surgical procedures or due to congenital, infectious orneoplastic processes. The tissue repair and sealing devices describedherein permit the positioning of a graft on an inner tissue surface anda deployable clasp on an outer tissue surface. Devices are deployed bymoving a clasp retain and release member along an applicator shaft torelease a deployable clasp and, thereby, to secure a graft to an innertissue surface; rapidly repair a tissue fenestration; and create apressure-resistant, watertight seal.

Description of the Related Art

Advances in endoscopic, robotic, and microsurgical technology havepermitted the rapid advancement of minimally invasive surgical (MIS)procedures whereby a surgical site is accessed through a small incision.For example, MIS procedures are used to access working spaces within abody cavity or body space (e.g., an abdominal cavity, a cranial sinus,an intracranial space, or a peri-spinal tissue) or a luminal pathway(e.g., a cardiovascular system; a gastrointestinal system; a cranial orspinal cerebrospinal fluid pathway; or an organ, such as a uterus, abladder, or a kidney).

Several factors common to MIS procedures, including limited workingspace, restricted surgical access, poor visualization, and the friablenature of certain tissues, make it difficult to repair and seal cuts,tears, or openings in tissues that are beneath the skin (collectivelytissue fenestrations). Failure to rapidly repair a tissue fenestrationand create a watertight seal can result in the leakage of body fluidsthrough the fenestrated tissue, which inhibits tissue healing, promotesinfection, and leads to substantial post-surgical morbidity.

Various devices and methodologies are available in the art for closingtissue fenestrations during MIS procedures including, in variouscombination: (a) suturing or stapling, (b) applying a tissue adhesive,and (c) positioning and adhering a tissue graft. Existing devices andmethodologies have limited practical utility, however, because theycannot rapidly repair tissue fenestrations and cannot reliably createpressure-resistant, watertight seals. As a result, healing of afenestrated tissue is inadequate and complications often arise from theleakage of body fluids, including blood (hemorrhage, hematoma masseffect), cerebrospinal fluid (meningitis, pneumocephalus, intracranialhypotension), gastrointestinal contents (infection, fistula), and urine(fistula, infection).

Direct suturing or stapling of tissue fenestrations is time-consumingand technically difficult in the limited space and restricted accessthat is characteristic of MIS procedures. As a consequence, the rapidrepair and creation of watertight seals is seldom achieved with therepair of tissue fenestrations produced during MIS procedures. Moreover,certain tissues that are encountered during MIS procedures are notamenable to suturing due to their friable nature, insufficient tissue topermit a complete closure, and close proximity to critical structures.And permanent metallic implants (i.e. staples) can interfere withsubsequent magnetic resonance imaging.

Absorbable and non-absorbable tissue adhesives, such as fibrin glue andpolyglycol gel, also have limited utility in the rapid repair of tissuefenestrations and creation of pressure-resistant, watertight seals.Tissue adhesives pose substantial technical challenges that cancontribute to poor surgical results, namely: (1) the required mixing andapplying of a rapidly-curing, two-component adhesive is difficult toperform in a small space; (2) buttressing of a graft with another tissue(e.g., fat) is often necessary; and (3) the bonding strength of tissueadhesives can be inadequate for the creation of a pressure-resistant,watertight seal.

Tissue patches, which include patches that are autologous (e.g., fasciaand fat), heterologous (e.g., bovine or porcine tissues), or synthetic(e.g., collagen matrix), require the use of sutures to hold in place andare susceptible to infection and tissue rejection. Pedicle graftoverlays to facilitate healing require a glue or buttress to ensureadherence, do not provide immediate watertight closure and areassociated with elevated surgical morbidity.

Existing devices for attaching grafts to the outer surface of tissuefenestrations have limited utility in MIS procedures. Devices that areknown in the art are difficult to manipulate and typically requireadditional procedures (e.g., harvesting a tissue for buttressing andplacing drains to reduce pressure gradients). Moreover, tissue graftsattached to an outer tissue surface, are prone to failure and areparticularly susceptible to pressure differentials between the insideand outside of a fenestrated tissue (e.g., a fenestrated blood vessel,dura mater, or gastrointestinal wall tissue). Because grafts positionedon an outer tissue surface often fail to repair tissue fenestrations andcreate watertight seals, fluids leak from a higher-pressure tissueinterior (e.g., blood, cerebrospinal fluid, or gastrointestinalcontents). This leads to poor healing, an elevated occurrence ofinfection, substantial post-surgical complications and morbidity, andprolonged hospitalization.

U.S. Pat. No. 5,634,944 (“Magram”) discloses a flanged graft employing agraft material that requires suturing to an adjacent tissue, such as thedura. PCT Patent Publication No. WO 2019/055551 (“Sansur”) discloses aheat-moldable resorbable bilayer sealing device that employs a patchthat is molded to fit over an outer surface of a tissue fenestration andsutured in place. PCT Patent Publication No. WO 2008/115849 (“Baird”)discloses a device that employs an anchoring element that is placedinside a tissue opening, a flexible membrane graft that is positionedoutside of the tissue opening, and a ratchet connector to secure theanchoring element to the flexible membrane and occlude the tissueopening.

U.S. Patent Publication No. 2015/0164489 (“Duggal”) discloses anexpandable barrier inserted through a defect into an interior space,then expanded and positioned against the inner surface. A secondbarrier, which may also be expandable, is positioned against the outersurface of the defect and connected to the inner barrier through aringed or notched bridging component.

U.S. Pat. No. 5,350,399 (“Erlebacher”) discloses a sealing device forthe repair of blood vessels (e.g., an arterial puncture) that employs aratcheted connector and a saw-toothed guide to secure intraluminal andextraluminal bioresorbable occluders in place to achieve fenestrationrepair.

U.S. Pat. No. 7,169,168 (“Muijs Van De More”) discloses a percutaneoussystem to seal arterial punctures in which an occluding element ispassed into the lumen using a guide wire and attached with a suture-likecomponent to secure an extraluminal element, thereby holding theoccluding element against the inner surface of the puncture site.

U.S. Pat. No. 8,105,352 (“Egnelov”) discloses a device for the sealingof a puncture hole in a vessel wall, which includes an inner componentthat is positioned on an interior vessel wall and an outer componentthat is positioned on an outer vessel wall. The inner and outercomponents are secured by a thread-like retaining element.

U.S. Patent Publication No. 20070093840 (“Rao”) discloses a devicehaving two opposing annular plates (i.e. an inner plate that is coupledto an outer plate) that clamp the peripheral edges of a tissue defect toachieve the watertight repair of a tissue defect. The two opposingannular plates are placed independently on either side of thefenestration via a mechanical attachment that secures their position. Aratcheted plate connector must be trimmed after the plates are broughttogether.

Despite the availability of existing technologies for closing tissuefenestrations during surgical procedures, there remains an unmet need inthe art for devices and methods that permit the rapid repair of tissuefenestrations and the reliable creation of pressure-resistant,watertight seals. The present disclosure fulfills these needs andprovides further related advantages over existing technologies that areunsuitable for use in minimally invasive surgical (MIS) procedures.

SUMMARY OF THE DISCLOSURE

Provided herein are tissue repair and sealing devices that exhibitunexpected and surprising advantages over devices and technologies thatare currently available in the art for repairing and sealing tissuefenestrations, including tissue fenestrations that occur duringminimally invasive surgical (MIS) procedures. Disclosed herein aretissue repair and sealing devices and methods for their use in both MISand open surgical (non-MIS) procedures to rapidly repair tissuefenestrations and reliably create watertight seals that are resistant topressure differentials such as those that occur across the inside andoutside of fenestrated tissues.

Within certain embodiments, the tissue repair and sealing devicesdisclosed herein comprise, in operable combination, (1) an applicatorassembly comprising a clasp retain and release member having a proximalend and a distal end, wherein the clasp retain and release member ismovably attached to an applicator shaft having a proximal end and adistal end, and (2) a detachable graft and clasp assembly (having agraft subassembly comprising a self-deploying graft that expands to itsoriginal shape after passage through a tissue fenestration) that isfixedly attached at or near its geometric center (a/k/a centroid) to adeployable clasp and coupler subassembly via a central coupler at/ornear the geometric center of a deployable clasp.

Certain embodiments of the tissue repair and sealing devices disclosedherein employ detachable graft and clasp assemblies comprising adeployable clasp and coupler subassembly having a central coupler and adeployable clasp having a plurality of radial struts or spokes thatemanate from the central coupler at or near the geometric center of thedetachable graft and clasp assembly. In certain aspects of theseembodiments, the detachable graft and clasp assembly attaches via thecentral coupler to the applicator assembly at the proximal end of theapplicator shaft. In further aspects, the device is deployed by slidingthe clasp retain and release member along the applicator shaft towardits distal end to, thereby, release the clasp from the retain andrelease member. Within still further aspects, when the device isdeployed, the clasp secures the graft to the inner tissue surface andthe clasp to the outer tissue surface to repair a tissue fenestrationand create a pressure-resistant, watertight seal.

In operation, tissue repair and sealing devices disclosed herein permitthe positioning of (1) a graft subassembly on an inner tissue surfaceand (2) a deployable clasp and coupler subassembly on an outer tissuesurface. Prior to use, a detachable graft and clasp assembly is attachedvia a central coupler to an applicator assembly at the proximal end ofan applicator shaft. The radial spokes or struts of a deployable claspare folded away from the graft subassembly and inserted into theproximal end of a clasp retain and release member to hold the deployableclasp in place. Using the applicator assembly, the graft subassembly isinserted through a tissue fenestration and positioned on an inner tissuesurface while the deployable clasp and coupler assembly remains outsideof the fenestrated tissue. The tissue repair and sealing devices aredeployed by moving the clasp retain and release member toward the distalend of the applicator shaft to release the deployable clasp, whichpermits the deployable clasp to unfold, apply pressure to the outertissue surface, secure the graft subassembly to the inner tissue surfaceand, thereby, to rapidly repair a tissue fenestration and reliablycreate a pressure-resistant, watertight seal.

Additional modifications of the tissue repair and sealing devices aredescribed herein that address specific technical problems encountered inMIS surgery. These include (1) variations in the size and shape of graftsubassemblies and deployable clasp and coupler subassemblies, (2)variations in the materials used for the graft subassemblies anddeployable clasp and coupler subassemblies, (3) configurations thatpermit the use of tissue repair and sealing devices in endoscopic orpercutaneous procedures (e.g., the use of conical graft elements andflexible applicator assemblies having a channel for accommodating aguide wire), and (4) the incorporation of drug-eluting matrix materialsin place of or in combination with the graft component to provide thecontinuous drug delivery at the site of application.

Exemplified herein are deployable devices that comprise a deployableclasp having a plurality of flexible spokes or struts that emanateradially from the coupler wherein the deployable clasp exhibits suitablebiophysical properties, size, shape, and dimensions to secure a graftthat is positioned on an inner tissue surface and a clasp that ispositioned on an outer tissue surface and to, thereby, repair a tissuefenestration and create a pressure-resistant, watertight seal.

Within some aspects, the tissue repair and sealing devices utilize adetachable graft and clasp assembly in which one or more elements of thegraft subassembly and/or the deployable clasp and coupler subassemblycomprise a biopolymer that exhibits shape memory and superelasticitycharacteristics including, for example, a biopolymer selected from thegroup consisting of a polylactide (PLA), a polyglycolide (PGA), apolylactide-co-D, L lactide (PDLLA), a polylactide-co-glycolide (PLGA),a polylactide-co-caprolactone (PLCL), a polycaprolactone (PCL), apolydioxanone (PDO), and a polylactide-co-trimethylene carbonate(PL-TMC). In certain applications, the biopolymer is a bioresorbablematerial.

Within further aspects, the tissue repair and sealing devices disclosedherein utilize a detachable graft and clasp assembly wherein the graftcomprises a material that is selected from the group consisting of anautograft, an isograft, an allograft, and a xenograft. In relatedaspects grafts are derived from an animal tissue selected from the groupconsisting of a human tissue, a bovine tissue, and a porcine tissue andinclude, for example, an animal tissue is selected from the groupconsisting dermis, pericardium, and intestine.

In related aspects, tissue repair and sealing devices utilize adetachable graft and clasp assembly wherein the graft comprises one ormore synthetic material(s), including, for example, a bioresorbablematerial such as poly(ethylene terephthalate) and/or expandedpolytetrafluoroethylene (ePTF).

In other related aspects, tissue repair and sealing devices utilize adetachable graft and clasp assembly wherein the graft comprises a duralsubstitute, including, for example, a dural substitute that is selectedfrom the group consisting of Duraform® dural graft implant, Biodesign®Dural Graft, DuraGen® Matrix, Cerafix dural Graft®, PRECLUDE®, LyoplantOnlay Graft®, Neuro-Patch Dural Graft®, SEAMDURA®, and Durepair™Regeneration Matrix.

In some aspects, a graft according to these embodiments can be anautograft, an isograft, an allograft, or a xenograft. In other aspects,the graft comprises a tissue, a membrane, a mesh, a matrix. In furtheraspects, the graft comprises a material that is an autologous,homologous, or heterologous material. In yet other aspects, the graftcomprises one or more synthetic material, including one or moresynthetic material selected from the group consisting of poly(ethyleneterephthalate) and expanded polytetrafluoroethylene (ePTF).

In still further aspects, the graft comprises a material that is derivedfrom an animal tissue, such as an animal tissue that is selected fromthe group consisting a human tissue, a bovine tissue, and a porcinetissue, including an animal tissue that is selected from the groupconsisting of dermis, pericardium, and intestine. Grafts according tothese embodiments may comprise one or more of the following: (1) anacellular, porous extracellular matrix scaffold; (2) collagen; (3)elastin; and (4) a growth factor. In some aspects, grafts according tothese embodiments comprise a mesh having a porosity that is sufficientto allow cells to enter, adhere, and undergo a cycle of remodeling.

In further aspects, grafts according to these embodiments comprise adural substitute, such as, for example, a dural substitute that isselected from the group consisting of Duraform® dural graft implant,Biodesign® Dural Graft, DuraGen® Matrix, Cerafix dural Graft®,PRECLUDE®, Lyoplant Onlay Graft®, Neuro-Patch Dural Graft®, SEAMDURA®,and Durepair™ Regeneration Matrix. In still further aspects, graftsaccording to these embodiments incorporate a drug-eluting matrix toprovide a continuous release of drugs to fluids and tissues at the siteof tissue repair and sealing.

Within yet other aspects, the tissue repair and sealing devicesdisclosed herein utilize a graft comprising an acellular, porousextracellular matrix scaffold of collagen, elastin, and, optionally, agrowth factor. Such grafts optionally comprise a mesh having a porositythat is sufficient to allow cells to enter, adhere, and undergo a cycleof remodeling. Grafts may additionally comprise a drug eluting matrix.

Within other aspects, the tissue repair and sealing devices disclosedherein utilize a detachable graft and clasp assembly in which one ormore elements of the graft subassembly and/or the deployable clasp andcoupler subassembly comprise comprises a biocompatible,non-ferromagnetic, passivated metal or metal alloy wire that exhibitsshape memory and superelasticity characteristics that permit the foldingof said metal or metal alloy while retaining the capacity to unfold to apre-folded state. Suitable biocompatible, non-ferromagnetic, passivatedmetal or metal alloy wires include wires comprising a metal or metalalloy that is selected from the group consisting of pure titanium; atitanium-based alloy; a cobalt-based alloy; a platinum-based alloy; anda molybdenum, tungsten, and tantalum alloy. Suitable metal or metalalloy having shape memory and superelasticity characteristics that areenhanced at elevated temperature include, for example, a nickel-titaniumalloy (Nitinol) and a niobium-titanium alloy.

Other embodiments on the present disclosure include methods for the useof the tissue repair and sealing devices disclosed herein in open(non-MIS) or minimally invasive surgical (MIS) procedures to rapidlyrepair tissue fenestrations and create pressure-resistant, watertightseals. Such methods include (a) selecting a tissue repair and sealingdevice having a detachable graft and clasp assembly removably attachedto an applicator assembly, wherein said detachable graft and claspassembly comprises a graft subassembly having a graft that is fixedlyattached to a deployable clasp and coupler subassembly having adeployable clasp with radial struts or spokes and a central coupler andwherein said applicator assembly comprises an applicator shaft, a claspretain and release member, and an actuator rod; (b) folding thedeployable clasp radial struts or spokes and and inserting into theclasp retain and release member; (c) inserting the graft through atissue fenestration and positioning the graft on an inner tissuesurface; (d) positioning the deployable clasp and coupler subassembly onan outer tissue surface; and (e) deploying the tissue repair and sealingdevice to release the deployable clasp from the clasp retain and releasemember to contact the outer tissue surface and secure the graft to theinner tissue surface, repairing the tissue fenestration, and create apressure-resistant, watertight seal.

The tissue repair and sealing devices and methods disclosed herein maybe employed in the direct visual, percutaneous, and/or endoscopic repairand sealing of a wide variety of human tissues. It will be understood bythose of skill in the art that the tissue repair and sealing devices andmethods described and exemplified herein may be modified withoutdeviating from the spirit and scope of the present disclosure and to,thereby, address problems specific to the nature, condition, andsurgical exposure of the fenestrated tissue. Such modifications may, forexample, include variations in the material composition and/ororientation of clasp to conform with unique characteristics of thefenestrated tissue. Modifications may also include (1) the addition of acomponent to enable the intraoperative substitution of different graftmaterials, (2) variations in the size and shape of the graft-clasp unit,and (3) a flexible applicator with or without a guide wire for thepercutaneous or endoscopic repair and sealing of punctures or ostomies.

These and other related aspects of the present disclosure will be betterunderstood in light of the following drawings and detailed description,which exemplify certain aspects of the various embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Certain aspects of the present disclosure will become more evident inreference to the drawings, which are presented for illustration, notlimitation.

FIG. 1 is a drawing that illustrates an exemplary tissue repair andsealing device according to one embodiment of the present disclosure. InFIG. 1A is shown an applicator assembly comprising an applicator shaftand a clasp retain and release member, wherein the clasp retain andrelease member is slidably connected to the applicator shaft. In FIG. 1Bis shown a detachable graft and clasp assembly comprising a graftsubassembly and a deployable clasp and coupler subassembly, whichcomprises a central coupler for attaching the detachable graft and claspsubassembly to the applicator assembly at a proximal end of anapplicator shaft. FIG. 1C is a CAD drawing showing a perspective view ofan exemplary tissue repair and sealing device as described in furtherdetail herein.

FIG. 2 is a drawing that shows the spatial arrangement of the componentparts of an exemplary detachable graft and clasp assembly wherein agraft subassembly is fixedly attached at its center to a deployableclasp and coupler subassembly via a central coupler. In FIG. 2, certainaspects of the detachable graft and clasp assembly include a deployableclasp and coupler subassembly comprising a deployable clasp having aplurality of struts or spokes that (1) emanate radially from the centralcoupler and (2) are in contact with a surface of the graft subassembly.In the particular graft subassembly shown in FIG. 2, the struts orspokes of the deployable clasp extend beyond the outer edge of the graftsubassembly to facilitate folding the deployable clasp and retaining bythe clasp retain and release member on the applicator assembly.

FIG. 3 illustrates a method for the use of a tissue repair and sealingdevice comprising a graft subassembly and deployable clasp and couplersubassembly as illustrated in FIGS. 1A-1C and FIG. 2 to rapidly repair atissue fenestration and create a pressure-resistant, watertight seal.FIG. 3A is a drawing that shows the retention of a deployable clasp andcoupler subassembly (according to FIGS. 1 and 2) by a clasp retain andrelease member of an applicator assembly. The deployable clasp andcoupler subassembly is folded at each of the plurality of radial strutsor spokes that emanate radially from central coupler and is insertedinto the proximal end of clasp retain and release member to retain thedeployable clasp in a folded configuration until the tissue repair andsealing device is deployed.

FIGS. 3B-3E are drawings that illustrate the use of a tissue repair andsealing device according to various embodiments of the presentdisclosure to rapidly repair a tissue fenestration and reliably create apressure-resistant, watertight seal. In FIG. 3B is shown a tissue repairand sealing device prior to insertion of a graft subassembly through atissue fenestration. The tissue repair and sealing device comprises anapplicator assembly attached to a detachable graft and clasp assembly inwhich the struts or spokes of a deployable clasp and coupler subassemblyare folded away from the graft subassembly and inserted into theproximal end of the clasp retain and release member. In FIG. 3C is shownthe tissue repair and sealing device of FIG. 3B after insertion of thegraft subassembly through the tissue fenestration. The graft subassemblyis positioned on an inner tissue surface while the deployable clasp andcoupler subassembly remains outside of the fenestrated tissue prior todeploying the tissue repair and sealing device. In FIG. 3D is shown thedeploying of the tissue repair and sealing device by sliding the claspretain and release member toward the proximal end of the applicatorshaft to, thereby, release the deployable clasp. In FIG. 3E is shown theseparation of the detachable graft and clasp assembly from theapplicator assembly and the positioning of the deployable clasp andcoupler assembly against an outer tissue surface to secure the graftsubassembly to the inner tissue surface and, thereby, to repair thetissue fenestration and create a pressure-resistant, watertight seal.

FIGS. 3F and 3G are photographs of an exemplary deployable clasp andcoupler prototype according to the embodiment presented in FIGS. 3A-3E,which was fabricated out of polyglycolic acid using a 3Dstereolithography (SLA) printer having a resolution of 25-50 microns.FIG. 3F shows the deployable clasp and coupler prototype in an openconfiguration and FIG. 3G shows the deployable clasp and coupler in aclosed configuration with the plurality of radial struts or spokesfolded for insertion into the proximal end of the clasp retain andrelease member. For purposes of illustration only, the deployable claspstruts or spokes are constrained by plastic tape to emphasize theconfiguration of the deployable clasp that is inserted into, andretained by, a clasp retain and release member that is movably connectedto an applicator shaft.

FIG. 4 is a drawing that shows an optional aspect of the various tissuerepair and sealing devices disclosed herein, wherein a central coupleris configured to be rotatably attached to a deployable clasp, whichpermits the angular rotation of the graft. In one exemplary aspectpresented in FIG. 4B, the central coupler is fabricated in a ball andsocket configuration, which permits the detachable graft and claspassembly to be oriented over a range of angles with respect to theapplicator shaft FIG. 4A as may be required during an MIS procedure.

FIG. 5 illustrates an embodiment of the presently disclosed tissuerepair and sealing device that is configured for use in surgicalprocedures (e.g., lumbar punctures and gastrostomies) to occlude alarge-bore needle puncture or percutaneous ostomy site. In FIG. 5A isshown a tissue repair and sealing device comprising an applicatorassembly having an applicator shaft and a clasp retain and releasemember and a detachable graft and clasp assembly having a graftsubassembly and a deployable clasp and coupler assembly, wherein thegraft is a conical occluder graft, wherein the applicator shaft isfabricated out of a flexible material, and wherein the applicator shaft,central coupler, and graft are configured with a central channel toaccommodate a guidewire. In certain aspects, the conical occluder graftis comprised of a bioabsorbable material. In FIG. 5B is shown thedeployment of tissue repair and sealing device according to theembodiment presented in FIG. 5A, wherein a conical occluder graft ispositioned on an inner tissue surface and the radial struts or spokes ofa deployable clasp are positioned on an outer tissue surface to applypressure against the outer tissue surface, secure the conical occludegraft, and, thereby, repair a tissue fenestration (i.e., a puncture orostomy site) and create a pressure-resistant, watertight seal.

FIGS. 5C-5G show an exemplary method by which a tissue repair andsealing device as shown in FIG. 5A is used to repair a puncture sitewith the use of a guidewire. As shown in FIG. 5C, a guidewire is passedthrough a large-bore needle that is inserted through a tissue barrierfor drainage of fluid. In an alternative aspect of this method, theguidewire may be passed through an indwelling catheter prior to itsremoval. After removal of the large-bore needle or indwelling catheter,the guidewire remains in place (FIG. 5D). FIG. 5E illustrates thepassage of the distal (external) end of the guidewire through thecentral channel within the conical occluder graft, central coupler, andapplicator shaft. The tissue repair and sealing device is advanced alongthe guidewire to the puncture site and the conical occluder graft ispassed through the puncture hole and positioned against the innersurface of the punctured tissue and the tissue repair and sealing deviceis deployed by moving the clasp retain and release member toward thedistal end of the applicator shaft to release the deployable clasp andcoupler subassembly (FIG. 5F). The deployable clasp is positionedagainst and applies pressure to the outer tissue surface to secure theconical occlude graft, repair the puncture, and create apressure-resistant, watertight seal. The applicator assembly is detachedfrom the detachable graft and clasp assembly, which remains at thepuncture site, and the applicator assembly is removed by sliding alongthe guidewire after which the guidewire is then removed (FIG. 5G).

FIG. 6 is a drawing that shows an optional aspect of the various tissuerepair and sealing devices disclosed herein. In FIG. 6A is shown anapplicator assembly comprising an applicator shaft and a clasp retainand release member, wherein the clasp retain and release member isslidably connected to the applicator shaft. FIG. 6B shows a detachablegraft and clasp assembly comprises a graft subassembly that includes aform ring adhered to one surface of the graft and wherein the form ringhas sufficient flexibility to permit the folding of the graft duringinsertion through a tissue fenestration and has sufficient rigidity toallow the graft to unfold (and assume its original shape) prior topositioning on an inner tissue surface. In some aspects of the presentdisclosure, which are described in further detain herein, the form ringcomprises a bioresorbable material.

FIG. 7 is a drawing that shows an optional aspect of the tissue repairand sealing devices presented in FIGS. 1-5 wherein the applicatorassembly (FIG. 7A) further comprises an actuator rod attached at one endto the clasp retain and release member and that extends past theapplicator shaft to permit the release from an extended distance of thedeployable clasp from the clasp retain and release member fromdetachable graft and clasp assembly (FIG. 7B).

FIG. 8 is a drawing that shows an optional aspect of the tissue repairand sealing devices that are presented in FIGS. 1-4 and 6-7 comprisingan applicator assembly (FIG. 8A) and a detachable graft and claspassembly (FIG. 8B), wherein the detachable graft and clasp assemblycomprises a graft subassembly that includes a form ring fixedly adheredto the graft and wherein the form ring has sufficient flexibility topermit the graft to fold during insertion through a tissue fenestrationand has sufficient rigidity to allow the graft to unfold prior topositioning on an inner tissue surface (as presented in FIG. 19) andwherein the graft overhangs the form ring to improve the adherence ofthe graft to an inner tissue surface.

FIG. 9 is a drawing that shows the spatial arrangement of the componentparts of an exemplary graft subassembly comprising a form ring fixedlyadhered to the inner surface of a graft. The exemplary form ring isshown in combination with ring stabilizing members and a central couplerreceiving member. The exemplary graft subassembly is shown with anorifice through which a central coupler receiving member protrudes.

FIG. 10 is a drawing that shows the spatial arrangement of the componentparts of an exemplary detachable graft and clasp assembly comprising agraft subassembly (as presented in FIG. 9) attached to a deployableclasp and coupler subassembly. The graft subassembly comprises a graftthat is fixedly adhered at an inner surface to a form ring having ringstabilizing members and a central coupler receiving member. In thisexemplary detachable graft and clasp assembly, the graft extends beyondthe circumference of the form ring to improve its contact with andadherence to an inner tissue surface. Deployable clasp and couplersubassembly is shown with a deployable clasp having a plurality ofradial spokes or struts that emanate from the central coupler. Thedeployable clasp and coupler subassembly is fixedly attached to centralcoupler to the graft subassembly via a central coupler receiving member.

FIG. 11 is a drawing that presents a view of deployable clasp andcoupler subassembly that shows a recess in the central coupler forattaching the center of the deployable clasp and coupler subassembly tothe center of the graft subassembly at a central coupler receivingmember as shown in FIG. 10.

FIG. 12 is a drawing that shows representative configurations of adetachable graft and clasp assembly comprising a graft subassembly (withor without a form ring or one or more ring stabilizing members) and adeployable clasp and coupler subassembly comprising a central couplerand a deployable clasp having a plurality of radial spokes or strutsemanating radially from a central coupler.

FIG. 13 is a drawing that shows various optional configurations of adetachable graft and clasp assembly that include a deployable clasp andcoupler subassembly having a plurality of radial spokes or struts topermit the optimization of the deployable clasp and coupler subassemblyfor use in securing a graft subassembly to an inner tissue surface torapidly repair tissue fenestrations of various size and within a varietyof distinct tissues and to, thereby, reliably create a watertight seal.

FIG. 13A is a drawing that shows a detachable graft and clasp assemblycomprising (1) a graft subassembly having a graft (with or without aform ring or ring stabilizing members) and (2) a deployable clasp andcoupler subassembly having a central coupler and a deployable clasphaving six (6) radial spokes or struts.

FIG. 13B is a drawing that shows a detachable graft and clasp assemblycomprising (1) a graft subassembly having a graft (with or without aform ring or ring stabilizing members) and (2) a deployable clasp andcoupler subassembly having a central coupler and a deployable clasphaving twelve (12) radial spokes or struts to increase the force exertedby the deployable clasp when securing a graft to an inner tissuesurface.

FIG. 13C is a drawing that shows a detachable graft and clasp assemblycomprising (1) a graft subassembly having a graft (with or without aform ring or ring stabilizing members) and (2) a deployable clasp andcoupler subassembly having a central coupler and a deployable clasphaving six radial spokes or struts, wherein each radial spoke or strutfurther comprises a lateral extension to improve the stability of thedeployable clasp and coupler subassembly.

FIG. 13D is a drawing that shows a detachable graft and clasp assemblycomprising (1) a graft subassembly having a graft (with or without aform ring or ring stabilizing members) and (2) a deployable clasp andcoupler subassembly having a central coupler and a deployable clasphaving six radial spokes or struts, wherein each radial spoke or strutfurther comprises a plurality of from 2 to 6 lateral extensions toincrease the stability of the deployable clasp and coupler subassembly.

FIG. 14 illustrates certain aspects of a detachable graft and claspassembly according to certain embodiments of the tissue repair andsealing devices presented herein. FIG. 14A is a line drawing that showsa detachable graft and clasp assembly comprising (1) a graft subassemblyhaving a graft (with or without a form ring or ring stabilizing members)and (2) a deployable clasp and coupler subassembly having a centralcoupler and a deployable clasp having six radial spokes or struts,wherein each radial spoke or strut is fabricated to have an increasedthickness, to curve away from the graft subassembly, and to include oneor more barbs on an end of each radial spoke or strut. FIG. 14B is a CADdrawing that shows various aspects of the detachable graft and claspassembly presented in FIG. 14C.

FIG. 15 is a drawing that shows the spatial arrangement of the componentparts of an exemplary graft subassembly according to an alternateembodiment of the present disclosure that permits the use of autologoustissue grafts, or the substitution at the time of surgery of othernon-rigid natural or synthetic graft materials in the tissue repair andsealing device. Within certain aspects of this embodiment, the graftsubassembly comprises a graft having a central orifice at or near thegeometric center for receiving a central coupler. The graft is attachedacross its inner surface to a form ring, which comprises a plurality ofring stabilizing members that emanate radially from a central couplerand a graft stabilizing prong to secure the graft subassembly.

FIG. 16 is a drawing that shows the spatial arrangement of the componentparts of certain aspects of an exemplary detachable graft and claspassembly according to an alternate embodiment of the present disclosurewherein a second form ring having a plurality of graft stabilizing prongalignment rings radially distributed along its inside circumference ispositioned over the outer surface of a graft such that it receives graftstabilizing prongs that protrude from form ring and that is attached toinner surface of the graft.

FIG. 17 is a drawing that shows the spatial arrangement of the componentparts of certain aspects of an exemplary detachable graft and claspassembly according to an alternate embodiment of the present disclosure(see, FIGS. 15 and 16) wherein the deployable clasp comprises a centralcoupler receiving ring and a plurality of radial spokes or struts thatemanate from the central coupler receiving ring.

FIG. 18 is a drawing that shows the folding of radial spokes or strutsthat emanate from one end of a central coupler receiving member of adeployable clasp and coupler subassembly in preparation for attaching toapplicator assembly and restraining with clasp retain and release memberaccording to the embodiment presented in FIGS. 15-17.

FIG. 19 is a schematic representation of an alternative embodiment ofthe tissue repair and sealing devices disclosed herein that isconfigured for providing continuous drug delivery to the fluid, tissue,or space within a body cavity, blood vessel, lumen or other structureswithin the body.

FIG. 20 illustrates an embodiment of a graft assembly in which the graftincludes a plurality of biocompatible, non-ferromagnetic, passivatedmetal or metal alloy wires, which exhibit shape memory andsuperelasticity characteristics to permit the folding of the metal ormetal alloy while retaining the capacity of the graft to unfold to apre-folded state. FIG. 20A illustrates one aspect of this embodimentwherein the plurality of biocompatible, non-ferromagnetic, passivatedmetal or metal alloy wires emanate radially from the central coupler. Asshown in FIG. 20B, the plurality of radial biocompatible,non-ferromagnetic, passivated metal or metal alloy wires permit thefolding of graft away from central coupler in an umbrella or parasolconfiguration. As shown in FIG. 20C, the plurality of radialbiocompatible, non-ferromagnetic, passivated metal or metal alloy wiresalso permits the further folding of the graft in a spiral configurationto reduce its diameter for insertion in a clasp retain and releasemember.

FIG. 21 illustrates a tissue repair and sealing device of the presentdisclosure that comprises (a) an applicator assembly having anapplicator shaft, an elongated clasp retain and release member, and anactuator rod connected to (b) a detachable graft and clasp assemblyhaving a graft subassembly and a deployable clasp and couplersubassembly (FIG. 21A). According to this embodiment detachable graftand clasp assembly utilizes a graft assembly as presented in FIG. 20wherein the graft includes a plurality of biocompatible,non-ferromagnetic, passivated metal or metal alloy wires, which exhibitshape memory and superelasticity characteristics, to permit the foldingof the metal or metal alloy while retaining the capacity to unfold to apre-folded state. FIG. 21B illustrates the tissue repair and sealingdevice of FIG. 21A in which both radial struts or spokes and graftsubassembly are folded and inserted into clasp retain and releasemember. FIG. 21C illustrates the further compacting of graft subassemblyby folding in a manner that permits radial biocompatible,non-ferromagnetic, passivated metal or metal alloy wires to adopt aspiral configuration, which is advantageous for fenestration repairstissues having limited space beneath the tissue barrier.

FIG. 22 illustrates a method for the use of a tissue repair and sealingdevice comprising a graft subassembly and deployable clasp and couplersubassembly as illustrated in FIGS. 20A-20C and FIGS. 21A-21C to rapidlyrepair a tissue fenestration and create a pressure-resistant, watertightseal. These tissue repair and sealing devices provide particularadvantages in the repair of fenestrated tissues having a small tissuefenestration and/or that are friable in nature. In this embodiment, thegraft subassembly is configured to include a plurality biocompatible,non-ferromagnetic, passivated metal or metal alloy wires, which exhibitshape memory and superelasticity characteristics, emanating radiallyfrom the center of the graft. Thus, the graft subassembly is configuredto easily deform to fit within clasp retain and release member and tore-expand to its original shape upon entering the inside of the tissueand moving of clasp retain and release member.

FIG. 22A illustrates an exemplary tissue repair and sealing device priorto deploying. Detachable graft and clasp assembly is attached toapplicator assembly at the proximal end of an applicator shaft and thefolded radial struts or spokes of a deployable clasp and couplersubassembly are retained at the proximal end of a clasp retain andrelease member. Prior to insertion of graft subassembly through a tissuefenestration, the radial struts or spokes of a deployable clasp andcoupler subassembly are folded away from the graft subassembly and alonga center of axis that passes through central coupler and inserted intothe proximal end of the clasp retain and release member. In thisembodiment is shown clasp retain and release member that is elongated toaccommodate graft subassembly, including a graft that comprises aplurality biocompatible, non-ferromagnetic, passivated metal or metalalloy wires that emanate radially from the center of the graft and thatis folded away from central coupler in an umbrella or parasolconfiguration and restrained by clasp retain and release member.

In FIG. 22B is shown the tissue repair and sealing device of FIGS.20A-20C and FIGS. 21A-21C after passage of the proximal end of claspretain and release member and graft subassembly though the tissuefenestration. In FIG. 22B is shown the deploying of graft subassembly bymoving clasp retain and release member along applicator shaft toward itsdistal end and stopping when the proximal end of clasp retain andrelease member reaches the outside of the fenestrated tissue. Graftsubassembly is then pulled back so that the graft contacts the innersurface of the fenestrated tissue while the deployable clasp and couplersubassembly remains outside of the fenestrated tissue and within claspretain and release member. In FIG. 22D is shown the release deployableclasp and coupler subassembly from clasp retain and release member bysliding the clasp retain and release member toward the distal end ofapplicator shaft to, thereby, release the deployable clasp struts orspokes, which snap back to their original configuration and applypressure against the outer surface of the fenestrated tissue, therebysecuring the graft in an optimal position to seal the fenestration. InFIG. 22E is shown the separation of the detachable graft and claspassembly from the applicator assembly and the positioning of thedeployable clasp and coupler assembly against an outer tissue surface tosecure the graft subassembly to the inner tissue surface and, thereby,to rapidly repair the tissue fenestration and reliably create apressure-resistant, watertight seal.

FIG. 23 illustrates various aspects of a pressure chamber used fortesting physical parameters of graft subassemblies for use in tissuerepair and sealing devices according to the present disclosure, whichallows for the establishment of internal fluid pressure waves thatcorrespond to fluid in various human body compartments. FIG. 23A is aphotograph and FIG. 23B is a CAD drawing of an in vitro pressure chamberused for testing the ability of graft subassemblies for use in tissuerepair and sealing devices to maintain a watertight seal at supranormalpressures. As shown in FIG. 23B, the pressure chamber 160 comprises awaveform generator 141, an opening 143 for placement of a graft sample,acrylic plates 145 to secure the graft sample, a pressure sensor 147,and a water inlet 149.

The in vitro pressure chamber enables the production of internal fluidpressure waves which correspond to fluid pressure waves in various humanbody compartments. In this example, porcine or ovine dura is placed inan opening and held between two acrylic places, with an embeddedpressure sensor to record continuous pressures in the chamber. Waveformsare produced in the chamber fluid to to reproduce the pulsatile pressurewaves found in various human tissue compartments. FIG. 23C is an in vivohuman CSF pressure waveform and FIG. 230 is an in vitro pressure chamberwaveform obtained with the pressure chamber shown in FIGS. 23′A-23B.

FIG. 24 is a graph of pressure-resistance data obtained with the invitro pressure chamber presented in FIG. 23 and testing a graftsubassembly comprising a DuraSecure graft material. This graph shows atypical measurement of pressure over time from the in vitro chamber torecapitulate human cerebrospinal fluid (CSF) within dura. In this case,the chamber pressure is initially brought to normal human CSF pressure(10 cm H₂O), then increased stepwise at increments of 2 cm H₂O untilpathologic elevated pressures (>20 cm H₂O) are achieved, then maintainedfor an additional 2 minutes without pressure decrement, indicative of awatertight seal. These data demonstrate that this graft subassemblymaintained pressure over time with a step-wise increase from the normalin vivo pressure for human cerebrospinal fluid (i.e., 10 cm H₂O) andwithstood an elevated pressure of 25 cm H₂O for a period of two (2)minutes.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure provides tissue repair and sealing devices, andmethods for the use thereof in both MIS and non-MIS procedures, forrapidly repairing tissue fenestrations and reliably creatingpressure-resistant, watertight seals. Within certain embodiments, tissuerepair and sealing devices according to the present disclosure comprise(1) an applicator assembly having a clasp retain and release member(having a proximal end and a distal end) that is movably connected to anapplicator shaft (having a proximal end and a distal end) and (2) adetachable graft and clasp assembly comprising a graft subassembly thatis fixedly attached to a deployable clasp and coupler subassembly forpositioning a graft subassembly on an inner tissue surface and adeployable clasp and coupler subassembly on an outer tissue surface.Deploying the tissue repair and sealing device by moving the claspretain and release member along the applicator shaft toward its distalend releases the deployable clasp and coupler subassembly to positionthe clasp onto an outer tissue surface and to secure the graft onto aninner tissue surface to, thereby, achieve the rapid repair of a tissuefenestration and the reliable creation of a pressure-resistant,watertight seal.

This disclosure will be better understood in view of the followingdefinitions, which are provided for clarification and are not intendedto limit the scope of the subject matter that is disclosed herein.

Definitions

Unless specifically defined otherwise herein, each term used in thisdisclosure has the same meaning as it would to those having skill in therelevant art.

As used herein, the terms “minimally invasive surgery” and “MIS” areused interchangeably to refer to surgical procedures that avoid the useof open, invasive surgery in favor of closed or local surgery that limitthe size of incisions to lessen wound healing time, associated pain, andrisk of infection as compared to traditional “non-MIS” procedures. MISprocedures, such as such as endoscopy, laparoscopy, arthroscopy, involvethe use of laparoscopic devices and remote-controlled manipulation ofinstruments with indirect observation of the surgical field through anendoscope or similar device, such as neuroendoscopy. MIS procedures alsoinclude the use of hypodermic injection, and air-pressure injection,subdermal implants, refractive surgery, percutaneous surgery,cryosurgery, microsurgery, keyhole surgery, endovascular surgery usinginterventional radiology (such as angioplasty), coronarycatheterization, permanent placement of spinal and brain electrodes,stereotactic surgery, the Nuss procedure, radioactivity-based medicalimaging methods, such as gamma camera, positron emission tomography andSPECT (single photon emission tomography). Related procedures areimage-guided surgery, and robot-assisted surgery.

As used herein, the term “tissue barrier” refers to a layer of tissue inthe body that separates two body compartments. “Tissue barriers”function in vivo as both protective shields and gate keepers betweendifferent compartments (e.g., blood and tissue) and are created byspecialised membrane-associated proteins, located at the lateral plasmamembrane of epithelial and endothelial cells. By sealing theparacellular space, such barriers impede the free diffusion of solutesand molecules across epithelial and endothelial monolayers, therebycreating an organ-specific homeostatic milieu. Tissue barriers includetissues that comprise the meninges, dura of the nervous system,abdominal wall, muscle fascia, blood vessels, esophagus, oropharynx,stomach, small and large intestine, rectum, trachea, bronchus, heart,bladder, ureter, urethra, uterus, peritoneum, pleura, fallopian tube,sclera of the eye, synovium, tympanic membrane or the capsule of a solidorgan (e.g., kidney, liver, and pancreas), fluid or space contained bythe tissue barrier (blood, cerebrospinal fluid, gastrointestinalcontents, pleural cavity, peritoneal cavity, vitreous humor, inner ear,fallopian tube or joint space).

As used herein, the term “meninges” refers, collectively, to the threemembranes (the dura mater, arachnoid mater, and pia mater) that line theskull and vertebral canal, enclose the brain and spinal cord, andprotect the central nervous system. “Meningitis” is the inflammation ofthe meninges, which is typically caused by an infectious agent.

As used herein, the terms “dura” and “dura mater” are usedinterchangeably and refer to the outermost (i.e. closest to the skulland vertebrae) of the three layers of membrane called the meninges (i.e.the meningeal layers) that are made of dense irregular connectivetissue. “Dura mater” (a/k/a “pachymeninx”) is derived primarily from theneural crest cell population, with postnatal contributions of theparaxial mesoderm. “Dura mater” protects the central nervous system bysurrounding the brain and the spinal cord.

As used herein, the terms “arachnoid mater” and “pia mater” refer to thetwo inner meningeal layers that are enveloped by the “dura” or “duramater.” The “arachnoid mater” is interposed between the much thicker“dura mater” and the deeper “pia mater.” The “arachnoid mater” isseparated from the “pia mater” by the subarachnoid space and isresponsible for retaining cerebrospinal fluid (“CSF”) within thesubarachnoid space (“SAS”). The “pia mater” is a thin, water permeable,fibrous tissue that permits blood vessels to pass through and nourishthe brain. The “arachnoid mater” and “pia mater” are known collectivelyas the “leptomeninges” and have complex functions as barriers andfacilitators for the movement of fluid, solutes and cells at the surfaceof the CNS and of fluid and solutes within the CNS parenchyma. Reviewedby Weller et al., Acta Neumpathologica 135:363-385 (2018). Both the“arachnoid mater” and “pia mater” derive from the neural crest.

As used herein, the term “fenestration” refers to an opening in a bodytissue barrier, such as a cut, tear, puncture, defect, or other breach.A fenestration may be spontaneous (e.g., a cerebrospinal leak from acongenital defect); secondary (e.g., a tissue barrier that iscompromised by a tumor or infection); planned (e.g., an incision orpuncture of a blood vessel, dura mater, or outer wall of a body organ);or unplanned (e.g., inadvertent durotomy, intestinal breach, orlaceration of the wall of a body organ during a surgical procedure). Afenestration in a tissue barrier usually requires repair and sealing toprevent serious complications (e.g., infection, bleeding, and woundbreakdown). However, for MIS procedures, the combination of restrictedworking space and access vectors, limitation of vision, and the natureand consistency of the fenestrated tissue barrier, significantly limitdirect repair and sealing by traditional methods (e.g., suturing orstapling).

As used herein, the terms “durotomy,” “unintended durotomy,” and“incidental durotomy” refer to an unintended tear of the dura mater(dural tear) that commonly occurs during MIS procedures performed on thespine (e.g., lumbar micshaftiscectomy). The complexity of spinal MISprocedures contributes to the incidence of “durotomy.” Durotomy requireimmediate repair and watertight sealing to prevent post-surgicalcomplications, including leakage of cerebrospinal fluid with subsequentmeningitis, or the accumulation of air in the spinal canal (i.e.pneumorachis, aerorachia, or epidural emphysema), most commonly withinthe extradural or subarachnoid space with disruption of the surroundingdura mater.

As used herein, the term “graft” refers, generally, to tissues,membranes, meshes, matrices, and the like that exhibit suitablebiophysical properties and are of the appropriate size, shape, and otherdimensions for adhering to inner tissue surfaces, repairing tissuefenestrations, and creating pressure-resistant, watertight seals.“Grafts” may derive from natural sources such as animal organ tissuesand tissue barriers and include tissues from a donor that exhibit adefined genetic relationship to tissues from a recipient such as, forexample, autografts (tissue obtained from patient), isografts (tissueobtained from a monozygotic twin), allografts (tissue obtained fromanother person), or xenografts (tissue obtained from a non-human animalspecies). Grafts from such natural sources may be autologous,homologous, or heterologous and may incorporate one or more syntheticmaterial.

As used herein, the term “drug eluting graft” refers to graft materialsthat incorporate a drug eluting matrix to provide controlled focal drugrelease. Han and Lelkes, Focal Controlled Drug Delivery, Advances inDelivery Science and Technology (Springer, Boston, 2014).

As used herein, the term “non-resorbable” refers to materials that arenot broken down and absorbed by the body, and thus are intended forlong-term, structural applications. “Non-resorbable” materials includeimplantable polymers, such as polyethylene and polyketones (PEEK), phasepure β Tricalcium phosphate (TCP), and hydroxyapatite (HA).

As used herein, the term “bioresorbable” refers to materials that arebroken down and absorbed by the body, and thus do not need to be removedmanually. Biosorbable materials include polymers including biopolymers,and copolymers thereof, such as polylactide (PLA), polyglycolide (PGA),polylactide-co-D, L lactide (PDLLA), polylactide-co-glycolide (PLGA),polylactide-co-caprolactone (PLCL), polycaprolactone (PCL),polydioxanone (PDO), polylactide-co-trimethylene carbonate (PL-TMC)which can be customized to meet mechanical performance parameters,biocompatibility, and resorption rates.

As used herein, the terms “passivated metal” or “passivated metal alloy”refer to metals and metal alloys that are resistant to corrosion andexhibit enhanced biocompatibility as compared to the native metal ormetal alloy. Passivation may be achieved by applying an outer layer ofshield material as a microcoating on the exposed surface of the metal ormetal alloy.

Words and phrases using the singular or plural number also include theplural and singular number, respectively. For example, terms such as “a”or “an” and phrases such as “at least one” and “one or more” includeboth the singular and the plural. Terms that are intended to be “open”(including, for example, the words “comprise,” “comprising,” “include,”“including,” “have,” and “having,” and the like) are to be construed inan inclusive sense as opposed to an exclusive or exhaustive sense. Thatis, the term “including” should be interpreted as “including but notlimited to,” the term “includes” should be interpreted as “includes butis not limited to,” the term “having” should be interpreted as “havingat least.”

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Additionally, the terms “herein,” “above,” and “below,” and words ofsimilar import, when used in this application, shall refer to thisapplication as a whole and not to any particular portion of theapplication.

It will be further understood that where features or aspects of thedisclosure are described in terms of Markush groups, the disclosure isalso intended to be described in terms of any individual member orsubgroup of members of the Markush group. Similarly, all rangesdisclosed herein also encompass all possible sub-ranges and combinationsof sub-ranges and that language such as “between,” “up to,” “at least,”“greater than,” “less than,” and the like include the number recited inthe range and includes each individual member.

The practice of the present disclosure will employ conventionaltechniques and methodologies that are in common use in the field ofmedicine, in particular in conjunction with minimally invasive surgical(MIS) procedures and non-minimally invasive surgical (non-MIS)procedures. Such techniques and methodologies are explained fully intreatises on surgical procedures as well as the medical, scientific, andpatent literature. See, e.g., Hunter and Spight, “Atlas of MinimallyInvasive Surgical Operations” (McGraw-Hill Education, Inc., 2018); Jonesand Schwaltzberg, “Operative Endoscopic and Minimally Invasive Surgery”(CRC Press, 2019); and Nahai, “The Art of Aesthetic Surgery” (2^(nd)Ed., Thieme, 2010).

All references cited herein, whether supra or infra, including, but notlimited to, patents, patent applications, and patent publications,whether U.S., PCT, or non-U.S. foreign, and all technical, medical,and/or scientific publications are hereby incorporated by reference intheir entirety.

Tissue Repair and Sealing Devices

Provided herein are tissue repair and sealing devices that exhibitunexpected and surprising advantages over devices and technologies thatare currently available in the art for repairing and sealing tissuefenestrations, including tissue fenestrations that occur duringminimally invasive surgical (MIS) procedures. In operation, thepresently disclosed tissue repair and sealing devices (1) position agraft subassembly on an inner tissue surface and (2) position adeployable clasp on an outer tissue surface to secure the graft to theinner tissue surface and, thereby, to repair a tissue fenestration andcreate a pressure-resistant, watertight seal.

Within certain embodiments, the tissue repair and sealing devicesdisclosed herein comprise, in operable combination, (1) an applicatorassembly comprising a clasp retain and release member having a proximalend and a distal end, wherein the clasp retain and release member ismovably attached to an applicator shaft having a proximal end and adistal end, and (2) a detachable graft and clasp assembly having a graftsubassembly that is fixedly attached at or near its geometric center(a/k/a centroid) to a deployable clasp and coupler subassembly via acentral coupler at/or near the geometric center of a deployable clasp.

Certain embodiments of the tissue repair and sealing devices disclosedherein employ detachable graft and clasp assemblies comprising adeployable clasp and coupler subassembly having a central coupler and adeployable clasp having a plurality of radial struts or spokes thatemanate from the central coupler at or near the geometric center of thedetachable graft and clasp assembly. In certain aspects of theseembodiments, the detachable graft and clasp assembly attaches via thecentral coupler to the applicator assembly at the proximal end of theapplicator shaft. In further aspects, the device is deployed by slidingthe clasp retain and release member along the applicator shaft towardits distal end to, thereby, release the clasp from the retain andrelease member. Within still further aspects, when the device isdeployed, the clasp secures the graft to the inner tissue surface andthe clasp to the outer tissue surface to repair a tissue fenestrationand create a pressure-resistant, watertight seal.

In operation, tissue repair and sealing devices disclosed herein permitthe positioning of (1) a graft subassembly on an inner tissue surfaceand (2) a deployable clasp and coupler subassembly on an outer tissuesurface. Prior to use, a detachable graft and clasp assembly is attachedvia a central coupler to an applicator assembly at the proximal end ofan applicator shaft. The radial spokes or struts of a deployable claspare folded away from the graft subassembly and inserted into theproximal end of a clasp retain and release member to hold the deployableclasp in place. Using the applicator assembly, the graft subassembly isinserted through a tissue fenestration and positioned on an inner tissuesurface while the deployable clasp and coupler assembly remains outsideof the fenestrated tissue. The tissue repair and sealing devices aredeployed by moving the clasp retain and release member toward the distalend of the applicator shaft to release the deployable clasp, whichpermits the deployable clasp to unfold, apply pressure to the outertissue surface, secure the graft subassembly to the inner tissue surfaceand, thereby, to rapidly repair a tissue fenestration and reliablycreate a pressure-resistant, watertight seal.

Additional modifications of the tissue repair and sealing devices aredescribed herein that address specific technical problems encountered inMIS surgery. These include (1) variations in the size and shape of graftsubassemblies and deployable clasp and coupler subassemblies, (2)variations in the materials used for the graft subassemblies anddeployable clasp and coupler subassemblies, (3) rotation of the couplingcomponent such that the graft can be oriented such that it is notperpendicular to the applicator shaft, thereby improving line-of-sightvisualization of the fenestration during insertion of the graft, (4)configurations that permit the use of tissue repair and sealing devicesin endoscopic or percutaneous procedures (e.g., the use of conical graftelements and flexible applicator assemblies having a channel foraccommodating a guide wire), and (5) the incorporation of drug-elutingmatrix materials in place of or in combination with the graft componentto provide the continuous drug delivery at the site of application.

Exemplified herein are deployable devices that comprise a deployableclasp having a plurality of flexible spokes or struts that emanateradially from the coupler wherein the deployable clasp exhibits suitablebiophysical properties, size, shape, and dimensions to secure a graftthat is positioned on an inner tissue surface and a clasp that ispositioned on an outer tissue surface and to, thereby, repair a tissuefenestration and create a pressure-resistant, watertight seal.

FIG. 1 illustrates an exemplary tissue repair and sealing deviceaccording to one embodiment of the present disclosure. In FIG. 1A isshown an applicator assembly 20 comprising a clasp retain and releasemember 35 having a proximal end 37 and a distal end 39, wherein claspretain and release member 35 is slidably connected to applicator shaft25 having a proximal end 27 and a distal end 29. In FIG. 1B is shown adetachable graft and clasp assembly 50 comprising graft subassembly 55and deployable clasp and coupler subassembly 65, which comprises radialspokes or struts 77 and central coupler 67 for attaching detachablegraft and clasp assembly 50 to applicator assembly 20 at the proximalend 27 of applicator shaft 25.

Detachable graft and clasp assembly 50 presented in FIG. 1 is configuredfor positioning graft subassembly 55 on an inner tissue surface andpositioning deployable clasp and coupler subassembly 65 on an outertissue surface. Tissue repair and sealing devices according to theseembodiments are deployed by sliding clasp retain and release member 35toward the distal end 29 of applicator shaft 25 to release deployableclasp and coupler subassembly 65 from the proximal end 37 of claspretain and release member 35 and secure graft subassembly 55 to aninside tissue surface via deployable clasp and coupler subassembly 65 onan outside tissue surface to, thereby, repair a tissue fenestration andcreate a pressure-resistant, watertight seal.

In certain aspects of the embodiment presented in FIG. 1, applicatorshaft 25 is a low-profile, bayonetted, and/or cylindrical applicatorshaft. In other aspects of the embodiment presented in FIG. 1, claspretain and release member 35 is a cylindrical clasp retain and releasemember having a proximal end 37 and a distal end 39, wherein proximalend 37 is configured for receiving and retaining deployable clasp andcoupler subassembly 65 in a folded configuration (shown in FIG. 3). Infurther aspects of the embodiment presented in FIG. 1, graft subassembly55 comprises an integrated graft. In still further aspects of theembodiment presented in FIG. 1, deployable clasp and coupler subassembly65, is fabricated from one or more bioresorbable materials.

In use, a graft subassembly is selected based upon a visual assessmentof the size of a tissue fenestration and the physical characteristics(e.g., friable nature) of the surrounding tissue. The graft subassembly55 is inserted through the tissue fenestration into the space on theinside of the tissue barrier and is pulled back against the inner tissuesurface. The deployable clasp and coupler subassembly 65 is releasedfrom the applicator assembly 20 by sliding the clasp retain and releasemember 35 toward the distal end 29 of applicator shaft 25 to contact theouter tissue surface and secure the graft subassembly 55 to the innertissue surface and, thereby, repairing the tissue fenestration andcreating a pressure-resistant, watertight seal.

FIG. 2 illustrates the spatial arrangement of the component parts of anexemplary detachable graft and clasp assembly 50 wherein graftsubassembly 55 is fixedly attached at its center 59 to deployable claspand coupler subassembly 65 at a proximal side 69 of central coupler 67.In FIG. 2, certain aspects of exemplary detachable graft and claspassembly 50 are shown, which include, without limitation, a deployableclasp and coupler subassembly 65 comprising a deployable clasp having aplurality of struts or spokes 77 that emanate radially from the proximalend 69 of central coupler 67 and that are each in contact with an innersurface of graft 57, and, optionally, which extend beyond the outer edgeof graft subassembly 55.

FIG. 3A illustrates the retention of radial struts or spokes 77 ofdeployable clasp and coupler subassembly 65 (according to FIG. 1 andFIG. 2) at the proximal end 37 of clasp retain and release member 35.Deployable clasp and coupler subassembly 65 is folded at each of theplurality of radial struts or spokes 77 that emanate radially from thedistal side 71 of central coupler 67. The folded radial struts or spokes77 of deployable clasp and coupler subassembly 65 are inserted intoproximal end 37 of clasp retain and release member 35 to retaindeployable clasp and coupler subassembly 65 in a folded configurationuntil the tissue repair and sealing device is deployed.

FIGS. 3B-3E illustrate the use of a tissue repair and sealing devicecomprising (a) applicator assembly 20 having a clasp retain and releasemember 35 that is movably attached to applicator shaft 25 and actuatorrod 45 and (b) detachable graft and clasp assembly 50 having graftsubassembly 55 fixedly attached to deployable clasp and couplersubassembly 65 having a central coupler 67 and a plurality of radialstruts or spokes 77 as illustrated in FIG. 1 and FIG. 2 to rapidlyrepair a tissue fenestration and create a pressure-resistant, watertightseal. In FIG. 3B is shown a tissue repair and sealing device prior toinsertion of a graft subassembly 55 through a tissue fenestration. Thetissue repair and sealing device comprises an applicator assemblyattached to a detachable graft and clasp assembly in which the struts orspokes 77 of a deployable clasp and coupler subassembly are folded awayfrom the graft subassembly and inserted into the proximal end of theclasp retain and release member 35.

In FIG. 3C is shown the tissue repair and sealing device of FIG. 3Bafter insertion of the graft subassembly 55 through the tissuefenestration. The graft subassembly 55 is positioned on an inner tissuesurface while the deployable clasp and coupler subassembly remainsoutside of the fenestrated tissue prior to deploying the tissue repairand sealing device.

In FIG. 3D is shown the deploying of the tissue repair and sealingdevice by using actuator rod 45 to slide the clasp retain and releasemember 35 toward the distal end 29 of the applicator shaft 25 to,thereby, release the deployable clasp struts or spokes 77.

In FIG. 3E is shown the separation of the detachable graft and claspassembly from the applicator assembly and the positioning of thedeployable clasp and coupler assembly against an outer tissue surface tosecure the graft subassembly to the inner tissue surface and, thereby,to repair the tissue fenestration and create a pressure-resistant,watertight seal.

FIG. 3F and FIG. 3G are photographs of an exemplary deployable clasp andcoupler prototype according to the embodiment presented in FIGS. 3A-3E,which was fabricated out of polyglycolic acid using a 3Dstereolithography (SLA) printer having a resolution of 25-50 microns.FIG. 3F shows the deployable clasp 65 and central coupler 67 prototypewith struts or spokes 77 in an open configuration and FIG. 3G shows thedeployable clasp and coupler 65 in a closed configuration with theplurality of radial struts or spokes 77 folded for insertion into theproximal end of the clasp retain and release member

FIG. 4 illustrates an optional aspect of the various tissue repair andsealing devices disclosed herein wherein central coupler 67 isconfigured to be rotatably attached to deployable clasp 75 having aplurality of radial struts or spokes 77, which thereby permits itsangular rotation of graft subassembly 55. In one exemplary aspectpresented in FIG. 4B, central coupler 67 is fabricated in a ball andsocket configuration, which permits the detachable graft and claspassembly 50 to be oriented over a range of angles with respect to theapplicator shaft 25 of applicator assembly 20 (FIG. 4A) as may berequired during an MIS procedure (where access and visibility areconstrained) to rotate the detachable graft and clasp assembly 50.

FIG. 5 illustrates an embodiment of the presently disclosed tissuerepair and sealing device that is configured for use in surgicalprocedures (e.g., lumbar punctures and gastrostomies) to occlude alarge-bore needle puncture or percutaneous ostomy site. In FIG. 5A isshown a tissue repair and sealing device comprising (a) an applicatorassembly 20 having an applicator shaft 25 and a movably attached claspretain and release member 35 and (b) a detachable graft and claspassembly 50 having a graft subassembly 55 fixedly attached to adeployable clasp and coupler assembly 65, wherein the graft 57 is aconical occluder graft, wherein the applicator shaft 25 is fabricatedout of a flexible material, and wherein the applicator shaft 25, centralcoupler 67, and graft 57 are configured with a central channel 123 toaccommodate a guidewire. In certain aspects, the conical occluder graft57 is comprised of a bioabsorbable material. In FIG. 5B is shown thedeployment of tissue repair and sealing device according to theembodiment presented in FIG. 5A, wherein a conical occluder graft 57 ispositioned on an inner tissue surface and the radial struts or spokes 77of a deployable clasp 75 are positioned on an outer tissue surface toapply pressure against the outer tissue surface, secure the conicalocclude graft 57, and, thereby, repair a tissue fenestration (i.e., apuncture or ostomy site) and create a pressure-resistant, watertightseal.

FIG. 6 illustrates an optional aspect of the various tissue repair andsealing devices disclosed herein wherein detachable graft and claspassembly 50 comprises graft subassembly 55 that includes a form ring 61that is fixedly adhered to graft 57 and wherein form ring 61 hassufficient flexibility to permit graft 57 to fold during insertionthrough a tissue fenestration and having sufficient rigidity to allowgraft 57 to unfold once the tissue fenestration in traversed forpositioning on an inner tissue surface. In some aspects of the presentdisclosure, form ring 61 comprises a bioresorbable material.

FIG. 7 illustrates an optional aspect of the tissue repair and sealingdevices presented herein, including FIGS. 1-4 and 6, which comprisesapplicator assembly 20 (FIG. 7A) and detachable graft and clasp assembly50 (FIG. 7B), wherein applicator assembly 20 further comprises actuatorrod 45 having a proximal end 47 and a distal end 49, wherein actuatorrod 45 is attached at its proximal end 47 at the distal end 39 of claspretain and release member 35. In operation, actuator rod 45, whichextends past the distal end 29 of applicator shaft 25, permits therelease of radial spokes or struts 77 of deployable clasp 75 (asdepicted in FIG. 3) from the proximal end 37 of clasp retain and releasemember 35 from an extended distance from detachable graft and claspassembly.

FIG. 8 illustrates an optional aspect of the tissue repair and sealingdevices that are presented herein, including FIGS. 1-4 and 6-7, whichcomprises applicator assembly 20 (FIG. 8A) and detachable graft andclasp assembly 50 (FIG. 8B), wherein detachable graft and clasp assembly50 comprises graft subassembly 55 that includes a form ring 61 that isfixedly adhered to graft 57, wherein form ring 61 has sufficient shapememory and superelasticity characteristics to permit graft 57 to foldduring insertion through a tissue fenestration and to allow graft 57 tounfold once the tissue fenestration in traversed for positioning on aninner tissue surface (as presented in FIGS. 3B-3E) and wherein graft 57overhangs form ring 61 to improve the adherence of graft 57 to an innertissue surface.

FIG. 9 illustrates the spatial arrangement of the component parts of anexemplary graft subassembly 55 comprising form ring 61 fixedly adheredto inner surface 91 of graft 57. Exemplary form ring 61 is shown incombination with ring stabilizing members 62 and graft stabilizing prong63. In the exemplary graft subassembly 55 is shown orifice 60 throughwhich graft stabilizing prong 63 protrudes.

FIG. 10 illustrates the spatial arrangement of the component parts of anexemplary detachable graft and clasp assembly 50 comprising graftsubassembly 55 (as presented in FIG. 9) attached to deployable clasp andcoupler subassembly 65. As shown in FIG. 10, graft subassembly 55comprises graft 57 fixedly adhered at an inner surface to form ring 61,form ring stabilizing members 62, and graft stabilizing prong 63. Inthis exemplary detachable graft and clasp assembly 50, graft 57 extendsbeyond the perimeter of form ring 61 to improve its contact with andadherence to an inner tissue surface. Deployable clasp and couplersubassembly 65 is shown with a deployable clasp 75 having a plurality ofradial spokes or struts 77 that emanate from the proximal side 69 ofcentral coupler 67. Deployable clasp and coupler subassembly 65 fixedlyattaches at the proximal side 69 of central coupler 67 (shown in FIG.11) to graft subassembly 55 via graft stabilizing prong 63.

FIG. 11 illustrates a view of deployable clasp and coupler subassembly65 showing recess 70 at the proximal side 69 of central coupler 67 forattaching the center of deployable clasp and coupler subassembly 65 tothe center of graft subassembly 55 at graft stabilizing prong 63 asshown in FIG. 10.

FIG. 12 illustrates representative configurations of detachable graftand clasp assembly 50 comprising graft subassembly 55 (with or withoutform ring 61 or ring stabilizing members 62) and deployable clasp andcoupler subassembly 65 comprising a central coupler 67 and a deployableclasp 75 having a plurality of radial spokes or struts 77 emanatingradially from central coupler 67. The various sizes, shapes, andmaterials used in the production of graft subassembly 55 and deployableclasp and coupler subassembly 65 permits the selection of a detachablegraft and clasp assembly wherein the graft subassembly 55 can safelypass through a tissue fenestration, completely cover the defect on theinside tissue surface, and exhibit desirable bioresorbability, drugelution, and other biophysical properties for repairing the tissuefenestration and creating a pressure-resistant, watertight seal.

Regardless of the size, shape, and materials used in graft subassembly55 and deployable clasp and coupler subassembly 65, detachable graft andclasp assemblies 50 are designed for interchangeably attaching toapplicator assembly 20 at the proximal end 27 of applicator shaft 25 andeach detachable graft and clasp assembly 50 is configured for retentionby clasp retain and release member 35 of applicator assembly 20 (asdepicted herein) and for release of detachable graft and clasp assembly50 from clasp retain and release member 35 upon deploying applicatorassembly 20.

It will be understood by those of skill in the art that theinterchangeability of detachable graft and clasp assemblies 50 permitsthe surgeon to rapidly assess the suitability of various graftsubassembly configurations for repairing a given tissue fenestrationduring a surgical procedure at the time of positioning graft subassembly55 on an inner tissue surface and deployable clasp and couplersubassembly 65 on an outer tissue surface.

FIG. 13 illustrates various optional configurations of detachable graftand clasp assembly 50, which include deployable clasp and couplersubassemblies 65 having a plurality of radial spokes or struts 77 (e.g.,ranging from 6 radial spokes or struts to 12 radial spokes or struts) topermit the optimization of deployable clasp and coupler subassembly 65for use in securing a graft subassemblies 55 to an inner tissue surfaceto rapidly repair tissue fenestrations of various size and within avariety of distinct tissues and to, thereby, reliably create apressure-resistant watertight seal.

FIG. 13A illustrates detachable graft and clasp assembly 50 comprising(1) a graft subassembly 55 having a graft 57 (with or without a formring 61 or ring stabilizing members 62) and (2) a deployable clasp andcoupler subassembly 65 having a central coupler 67 and a deployableclasp 75 having six (6) radial spokes or struts 77.

FIG. 13B illustrates detachable graft and clasp assembly 50 comprising(1) a graft subassembly 55 having a graft 57 (with or without a formring 61 or ring stabilizing members 62) and (2) a deployable clasp andcoupler subassembly 65 having a central coupler 67 and a deployableclasp 75 having twelve (12) radial spokes or struts 77 to increase theforce exerted by deployable clasp 75 when securing graft 57 to an innertissue surface as can be required in a situation where there is a highpressure differential between the compartments inside versus outside ofthe fenestrated tissue.

FIG. 13C illustrates detachable graft and clasp assembly 50 comprising(1) a graft subassembly 55 having a graft 57 (with or without a formring 61 or ring stabilizing members 62) and (2) a deployable clasp andcoupler subassembly 65 having a central coupler 67 and a deployableclasp 75 having six radial spokes or struts 77, wherein each radialspoke or strut 77 further comprises a lateral extension 79 to improvethe stability of deployable clasp and coupler subassembly 65 as may berequired when a fenestrated tissue is friable at the site of attachmentor exhibits multiple fenestrations.

FIG. 13D illustrates detachable graft and clasp assembly 50 comprising(1) a graft subassembly 55 having a graft 57 (with or without a formring 61 or ring stabilizing members 62) and (2) a deployable clasp andcoupler subassembly 65 having a central coupler 67 and a deployableclasp 75 having six radial spokes or struts 77, wherein each radialspoke or strut 77 further comprises a plurality of from two (2) to six(6) lateral extensions 79, which improves the stability of deployableclasp and coupler subassembly 65 as may be required when a fenestratedtissue is friable at the site of attachment or exhibits multiplefenestrations.

FIG. 14A illustrates detachable graft and clasp assembly 50 comprising(1) a graft subassembly 55 having a graft 57 (with or without a formring 61 or ring stabilizing members 62) and (2) a deployable clasp andcoupler subassembly 65 having a central coupler 67 and a deployableclasp 75 having six radial spokes or struts 77, wherein each radialspoke or strut 77 is fabricated to have increased thickness, to curveaway from graft subassembly 55, and to include a barbs 81 on the distalend 80 at each radial spoke or strut 77 to improve the attachment of theconstruct to the underlying tissue. FIG. 14B is a CAD drawing of adetachable graft and clasp assembly 50 (as illustrated in FIG. 14A) thatcomprises arched spokes or struts and a dura lock channel and that maybe fabricated out of PLGA or other suitable biocompatible and/orbioresorbable material that exhibits one or more of the desiredmechanical properties presented in Table 1. It will be appreciated bythose having skill in the art that the increased thickness and curvingof radial spoke or strut 77 and/or addition of barb 81 can beadvantageously employed in less collatenous fenestrated tissue (e.g.,bowel mucosa) where the curved struts exert greater pressure on theouter tissue surface and barbs 81 permit radial spokes or struts 77strut tips to slightly penetrate the tissue at site of application. FIG.14C is an exemplary detachable graft and curved clasp assembly 50 thatwas fabricated with PLGA using a 3D printer.

FIG. 15 illustrates the spatial arrangement of the component parts of anexemplary graft subassembly 55 according to an alternate embodiment ofthe present disclosure that permits the use of autologous tissue grafts,or the substitution at the time of surgery of other non-rigid natural orsynthetic graft materials in the tissue repair and sealing device. Fornon-rigid grafts, especially autologous grafts, accurate positioning ofgraft 57 against the inner surface of a fenestrated tissue and completecoverage of the entire opening can be difficult and graft 57 can fold ordeform after passage through the fenestration.

Within certain aspects of this embodiment, graft subassembly 55comprises a graft 57 having a central orifice 60 at or near thegeometric center for receiving central coupler 67. Graft 57 is attachedacross its inner surface 91 to form ring 61, which comprises a pluralityof ring stabilizing members 62 (1) each emanating radially from acentral coupler 67 and (2) each having at its distal end a graftstabilizing prong 64. It will be understood that form ring 61 hassufficient flexibility to permit graft 57 to fold during passage througha tissue fenestration and sufficient rigidity to return graft 57 to itsoriginal flat shape for positioning on an inner tissue surface.

FIG. 16 illustrates the spatial arrangement of the component parts ofcertain aspects of an exemplary detachable graft and clasp assembly 50,according to an alternate embodiment of the present disclosure, whereina second form ring 61 having a plurality of graft stabilizing prongalignment rings 68 radially distributed along its inside circumferenceis positioned over outer surface 92 of graft 57 such that it receivesgraft stabilizing prongs 64 that protrude from form ring 61 and that isattached to inner surface 91 of graft 57.

FIG. 17 illustrates the spatial arrangement of the component parts ofcertain aspects of an exemplary detachable graft and clasp assembly 50,according to an alternate embodiment of the present disclosure (See,FIGS. 15 and 16), wherein deployable clasp 75 comprises central couplerreceiving ring 95 and a plurality of radial spokes or struts 77, eachhaving a distal end 80, which emanate from central coupler receivingring 95.

The detachable graft and clasp assembly 50 presented in FIGS. 15-17 willfind particular utility in the presently disclosed tissue repair andsealing devices in those clinical applications wherein, during thecourse of a surgical procedure, it is desirable to substitute one graft57, such as a first graft 57 comprising an autologous, homologous,heterologous or synthetic graft material, with a second graft 57, suchas a second graft 57 comprising an autologous, homologous, heterologousor synthetic graft material. An autologous graft may, for example,comprise a patient tissue that is harvested contemporaneously with thesurgical procedure. Thus, graft subassembly 55 may employ a graft 57that is fabricated from tissue harvested from from a patient's fascia,pericranium, mucosa or skin. Alternatively graft 57 may comprise ahomologous, heterologous or synthetic graft material, which cansubstituted in the device by the method described for autologous grafts,according to the clinical setting.

In use, graft 57 is cut into a circular shape and fashioned with centralorifice 60 to accommodate the passage of central coupler 67 through thecenter of graft 57. The graft is then attached at the outercircumference of its inner surface 91 to form ring 61 comprising aplurality of graft stabilizing prongs 64. A second form ring 61comprising a plurality of graft stabilizing prong alignment rings 68 isattached to outer graft surface 92 along its circumference. A deformableclasp 75 is then placed over the second form ring 61 to securedeformable clasp 75 at central coupler receiving member 101 to centralcoupler 67.

FIG. 18 illustrates the folding of radial spokes or struts 77 thatemanate at the proximal end from central coupler receiving member 101 ofdeployable clasp and coupler subassembly 65 in preparation for attachingto applicator assembly 20 and restraining with clasp retain and releasemember 35.

FIG. 19 is a schematic representation of an alternative embodiment ofthe tissue repair and sealing devices disclosed herein that isconfigured for providing continuous drug delivery to the fluid, tissue,or space within a body cavity, blood vessel, lumen or other structureswithin the body. In this embodiment, the graft 57 is either replacedwith, or incorporates, a drug-eluting matrix, such as a bioresorbabledrug-eluting matrix for delivery of a drug or agent to an inner tissuesurface and/or for continuous release into the blood, body fluids, ortissue parenchyma in contact with the matrix.

FIG. 20 illustrates an embodiment of a graft assembly 55 in which graft57 includes a plurality of biocompatible, non-ferromagnetic, passivatedmetal or metal alloy wires 64, which exhibit shape memory andsuperelasticity characteristics to permit the folding of the metal ormetal alloy while retaining the capacity of graft 57 to unfold to apre-folded state. FIG. 20A illustrates one aspect of this embodimentwherein the plurality of biocompatible, non-ferromagnetic, passivatedmetal or metal alloy wires 64 emanate radially from central coupler 67.As shown in FIG. 20B, the plurality of radial biocompatible,non-ferromagnetic, passivated metal or metal alloy wires 64 permit thefolding of graft 57 away from central coupler 67 in an umbrella orparasol configuration. As shown in FIG. 20C, the plurality of radialbiocompatible, non-ferromagnetic, passivated metal or metal alloy wires64 also permits the further (or alternative) folding of graft 57 in aspiral configuration to reduce its diameter for insertion in a claspretain and release member 35.

FIG. 21A illustrates a tissue repair and sealing device of the presentdisclosure that comprises (a) an applicator assembly 20 having anapplicator shaft 25, an elongated clasp retain and release member 35,and an actuator rod 45 connected to (b) a detachable graft and claspassembly 50 having a graft subassembly 55 and a deployable clasp andcoupler subassembly 65. According to this embodiment detachable graftand clasp assembly 50 utilizes a graft assembly 55 as presented in FIG.20 wherein graft 57 includes a plurality of biocompatible,non-ferromagnetic, passivated metal or metal alloy wires 64, whichexhibit shape memory and superelasticity characteristics, to permit thefolding of the metal or metal alloy while retaining the capacity tounfold to a pre-folded state. FIG. 21B illustrates the tissue repair andsealing device of FIG. 21A in which both radial struts or spokes 77 andgraft subassembly 55 are folded and inserted into clasp retain andrelease member 35. FIG. 21C illustrates the further compacting of graftsubassembly 55 by folding in a manner that permits radial biocompatible,non-ferromagnetic, passivated metal or metal alloy wires 64 to adopt aspiral configuration, which is advantageous for fenestration repairstissues having limited space beneath the tissue barrier.

1. Grafts for Use in Tissue Repair and Sealing Devices

Within certain aspects, the tissue repair and sealing devices disclosedherein comprise a graft that is either directly incorporated (i.e.,“integrated”) into the detachable graft and clasp assembly or issubstituted at the time of surgery using the form rings as describedherein. Tissue repair and sealing devices according to this disclosuremay employ a fixed central coupler that maintains the detachable graftand clasp assembly in a perpendicular orientation relative to theapplicator assembly or may employ an adjustable central coupler thatpermits movement of the detachable graft and clasp assembly relative toapplicator assembly for use in enhancing the visibility of the tissuefenestration and nearby structures.

As used herein, the term “graft” refers, generally, to tissues,membranes, meshes, matrices, and the like that exhibit suitablebiophysical properties and are of the appropriate size, shape, and otherdimensions for adhering to inner tissue surfaces, repairing tissuefenestrations, and creating pressure-resistant, watertight seals.“Grafts” may derive from natural sources such as animal organ tissuesand tissue barriers and include tissues from a donor that exhibit adefined genetic relationship to tissues from a recipient such as, forexample, autografts (tissue obtained from patient), isografts (tissueobtained from a monozygotic twin), allografts (tissue obtained fromanother person), or xenografts (tissue obtained from a non-human animalspecies). Grafts from such natural sources may be autologous,homologous, or heterologous and may incorporate one or more syntheticmaterial.

As used herein, the term “synthetic mesh” refers to a graft made fromnon-biologic materials including poly(ethylene terephthalate) (a/k/aDacron®) or expanded polytetrafluorethylene (ePTFE, Goretex®) and aredescribed in Patera and Schoen, Biomaterials Science pp. 470-494(Elsevier Academic Press, San DEieto, Calif. (2004)). “Synthetic meshes”are often permanent in nature, do not undergo bioresorption, and areassociated with chronic inflammation and foreign body reactions,firmness and fibrosis, and infection. Schmatz, Cureus 10(1):e2127 (2018)provides a report on surgical experience with an synthetic, biosorbablegraft material that has received FDA approval.

As used herein, the term “biologic mesh” refers to a graft that isderived from animal tissue, typically human or porcine dermis, andprocessed to an acellular, porous extracellular matrix scaffold ofcollagen and elastin. Often a “biological mesh” contains growth factorsfrom the source tissue, which attract endothelial cells and fibroblasts,which release additional chemoattractants that signal the migration ofother structural cells. The three-dimensional nature and porosity of“biological meshes” allow cells (mainly fibroblasts and inflammatorycells) to enter the mesh and adhere and undergo a cycle of remodelingconsisting of degradation of the biologic mesh and regeneration of thecollagen scaffold with host tissue. The balance of this degradation andrebuilding process, and the speed with which it occurs, influences theultimate strength and structure of the repaired tissue. “Biologicmeshes” can be crosslinked to increase graft firmness, although greatercell infiltration is typically observed with biologic meshes that arenot crosslinked. Crosslinking can also prevent collagen breakdown andinhibit macrophage migration, which poses and increased risk ofinfection.

As used herein, the term “dural substitute” refers to a graft, eithersynthetic or biologic, for use in sealing dural tissue fenestrations byabsorbing and integrating onto the patient's tissue to prevent CSF leaksand to allow openings in the dura to heal after surgery. “Duralsubstitutes” that may be advantageously employed in the tissue repairand sealing devices disclosed herein include the Duraform® dural graftimplant (Natus, Medical Inc., Middleton, Wis.), which is acollagen-based biocompatible material with high tensile strength that ismanufactured from processed bovine tendons; the Biodesign® Dural Graftand Duraplasty graft (Cook Medical, Bloomington, Ind.), which employ anatural extracellular matrix (ECM) derived from porcine small intestinalsubmucosa (SIS); DuraGen® Matrix (Integra LifeSciences, Princeton,N.J.), which is a collagen matrix; Cerafix dural Graft®, which is asynthetic, resorbable material; PRECLUDE Dura Substitute®, which is aninert elastomeric fluoropolymer (ePTFE): Lyoplant Onlay Graft®, which isan absorbable collagen bilayer: Neuro-Patch Dural Graft®, which ismicroporous fleece; SEAMDURA®, which is a copolymeric film layered withPGA; and Durepair™ Regeneration Matrix (Medtronic, Minneapolis, Minn.),which is a non-synthetic collagen matrix derived from Type III fetalbovine tissue.

As used herein, the term “drug eluting graft” refers to graft materialsthat incorporate a drug eluting matrix to provide controlled focal drugrelease. Han and Lelkes, Focal Controlled Drug Delivery, Advances inDelivery Science and Technology (Springer, Boston, 2014).

As used herein, the term “non-resorbable” refers to materials that arenot broken down and absorbed by the body, and thus are intended forlong-term, structural applications. “non-resorbable” materials includeimplantable polymers, such as polyethylene and polyketones (PEEK), phasepure Tricalcium phosphate (TCP), and hydroxyapatite (HA).

In one embodiment, the graft material without support is flexible enoughto be passed through the tissue defect, but also firm enough to retainits shape during positioning. In another embodiment, there is a thinbioresorbable form ring bonded to the outer circumference of the graft5, which is flexible enough to deform during passage through the defect,then return to its original shape on the inner surface of the tissue.Attached to the center of the graft is a coupling component 6, allowingattachment and detachment of the applicator shaft.

In certain deployable devices according to these embodiments, thedeployable clasp is fabricated from a flexible, bendable, andcompressible material. Within further aspects, the flexible, bendable,and compressible material is a bioresorbable material, such as abioresorbable material comprising one or more biopolymer, including oneor more biopolymer that is selected from the group consisting of apolylactide (PLA), a polyglycolide (PGA), a polylactide-co-D, L lactide(PDLLA), a polylactide-co-glycolide (PLGA), apolylactide-co-caprolactone (PLCL), a polycaprolactone (PCL), apolydioxanone (PDO), and a polylactide-co-trimethylene carbonate(PL-TMC).

Exemplified herein are deployable devices that comprise a deployableclasp having a plurality of flexible spokes or struts that emanateradially from the coupler wherein the deployable clasp exhibits suitablebiophysical properties, size, shape, and dimensions to secure a graftthat is positioned on an inner tissue surface and a clasp that ispositioned on an outer tissue surface to, thereby, repair a tissuefenestration and create a pressure-resistant, watertight seal.

In certain deployable devices according to these embodiments, the graftcomprises a flexible, bendable, firm, and compressible material. In someaspects of these embodiments the graft exhibits shape memory andsuperelasticity characteristics. Grafts according to these embodiments,when used in combination with a deployable clasp, are suitably employedfor the repair of tissue fenestrations and creation ofpressure-resistant, watertight seals when the graft is positioned on aninner tissue surface and secured with a deployable clasp on an outertissue surface.

In certain aspects, a graft according to these embodiments can be anautograft, an isograft, an allograft, or a xenograft. In other aspects,the graft comprises a tissue, a membrane, a mesh, a matrix. In furtheraspects, the graft comprises a material that is an autologous,homologous, or heterologous material. In yet other aspects, the graftcomprises one or more synthetic material, including one or moresynthetic materials selected from the group consisting of poly(ethyleneterephthalate) and expanded polytetrafluoroethylene (ePTF). In stillfurther aspects, the graft comprises a material that is derived from ananimal tissue, such as an animal tissue that is selected from the groupconsisting a human tissue, a bovine tissue, and a porcine tissue or ananimal tissue that is selected from the group consisting of dermis, andintestine. Grafts according to these embodiments may comprise anacellular, porous extracellular matrix scaffold of collagen, elastin,and, optionally, a growth factor. In some aspects, grafts according tothese embodiments comprises a mesh having a porosity that is sufficientto allow cells to enter, adhere, and undergo a cycle of remodeling.

In other aspects, grafts according to these embodiments are fabricatedout of a flexible, bendable, firm, and compressible material that is abioresorbable material, including a bioresorbable material comprisingone or more biopolymer, such as a biopolymer that is selected from thegroup consisting of a polylactide (PLA), a polyglycolide (PGA), apolylactide-co-D, L lactide (PDLLA), a polylactide-co-glycolide (PLGA),a polylactide-co-caprolactone (PLCL), a polycaprolactone (PCL), apolydioxanone (PDO), and a polylactide-co-trimethylene carbonate(PL-TMC).

In further aspects, grafts according to these embodiments comprise adural substitute, such as, for example, a dural substitute that isselected from the group consisting of Duraform® dural graft implant,Biodesign® Dural Graft, DuraGen® Matrix, Cerafix dural Graft®,PRECLUDE®, Lyoplant Onlay Graft®, Neuro-Patch Dural Graft®, SEAMDURA®,and Durepair™ Regeneration Matrix.

The devices and methods described herein may be applied to directvisual, percutaneous, or endoscopic repair and sealing of multipletissues in the body. In addition, the device and methods describedherein may be modified to address problems specific to the nature,condition and surgical exposure of the fenestrated tissue, includingvariations of the clasp material and orientation, a component to enablethe intraoperative substitution of different graft materials, variationsin the size and shape of the graft-clasp unit, and percutaneous orendoscopic repair and sealing of punctures or ostomies using a flexibleapplicator with or without guide wire.

Prior to using the repair and sealing device, the deployable clasp isfolded and inserted into the slidably attached clasp retain and releasemember. Upon positioning of the graft on the inner tissue surface of thefenestrated tissue and the clasp on the outer tissue surface, the deviceis deployed by sliding the clasp retain and release member along theapplicator shaft toward its distal end. When the device is deployed, theclasp struts or spokes are released from the clasp retain and releasemember and contact the outer tissue surface of the fenestrated tissue,thereby securing the graft and clasp in place to repair the tissuefenestration and create a watertight seal.

Additional modifications of the tissue repair and sealing device aredescribed herein which address specific technical problems encounteredin MIS surgery. These include variations in graft-clasp unit size andshape, a rotational attachment at the coupling devive to enablepositioning of the graft relative to the applicator to improve line ofvision and access, variations in the strut materials and configuration,use of a flexible applicator and guide wire channel for use of thedevice in endoscopic or percutaneous procedures, and the incorporationof drug-eluting matrix materials in the graft component to providecontinuous drug delivery at the site of application.

Thus, within certain embodiments, the tissue repair and sealing devicesdescribed herein incorporate a drug-eluting matrix to provide acontinuous release of drugs to fluids and tissues at the site of tissuerepair and sealing. In FIG. 19 is illustrated an exemplary tissue repairand sealing device in which graft 57 incorporates, or replaced with, abioresorbable drug-eluting matrix to provide continuous drug delivery tothe fluid, tissue or space within a body cavity, blood vessel, lumen orother structures within the body. By placing the drug-eluting matrix onthe inner tissue surface, drugs or agents of many types can be locallyand continuously released into blood, body fluids, or tissue parenchymain contact with the matrix. The device can be either rigid or flexibleas above, and passed under direct vision, by endoscope, or by apercutaneous approach using a guide wire.

The tissue repair and sealing devices may be adapted for use in securinga drug-eluting matrix, or a graft that incorporates a drug-elutingmatrix, to an inner tissue surface including, without limitation, atissue selected from dura, blood vessel, wall of esophagus, stomach orintestine, bladder wall, ureter, peritoneum, pleura, uterus, Fallopiantube, sclera of the eye, synovium, tympanic membrane or the capsule of asolid organ. Drugs that are incorporated into a drug-eluting matrix arereleased into the fluid or space contained by the tissue barrier (blood,cerebrospinal fluid, gastrointestinal contents, pleural cavity,peritoneal cavity, vitreous humor, inner ear, Fallopian tube or jointspace) and can be fashioned to disperse drugs at a pre-determined rateand concentration based upon the nature of the drug, the target tissue,and the chemical composition of the drug-eluting matrix to achieve theintended therapeutic effect.

In certain embodiments, tissue repair and sealing devices as disclosedherein may be advantageously employed to provide the continuous deliveryof therapeutic agents to the bloodstream via arteries or veins forsystemic distribution, to the bloodstream of arteries serving tissuesdistal to the implant to produce a localized effect in those downstreamtissues while minimizing systemic distribution, or to fluids and/ortissues within a cavity or space. In certain applications, the drug thatis released can act locally and directly upon the tissue to which thedrug-eluting matrix, or graft comprising a drug-eluting matrix, issecured. Thus, the present disclosure contemplates the use of the tissuerepair and sealing devices disclosed herein for use in providing thelocal delivery of agents to promote healing, to prevent local cellularproliferation (e.g., intimal proliferation or excess scar formation), toprovide local anesthesia, to inhibit fertilization, or to treatinfection with antimicrobial agents. For either embodiment, thebioresorbable nature of the repair and sealing device and drug matrixwould eliminate the need for removal of the device at the conclusion oftherapy.

Drug-eluting matrices and grafts have been described in the art that maybe adapted for use in the presently disclosed tissue repair and sealingdevices. See, for example, Alvarez-Lorenzo, Journal of Pharmacology andExperimental Therapeutics 370:544 (2019) (describing implantable smartdrug release devices and materials); Concheiro, Advanced Drug DeliveryReview 65(9):1188 (2013) (describing chemically cross-linked and graftedcyclodextrin hydrogels for use in drug-eluting medical devices); Nie,Journal of Materials Chemistry 7:6515 (2019) (describing integratedgrafts comprising a biologically developed cartilage-bone interface ofosteochondural defect repair); Zilberman, 299 (Springer-Verlag 2010)(reviewing drug-eluting medical implants, including drug-elutingmatrices and grafts); Zilberman, Journal of Controlled Release130(3):202 (2008) (describing antibiotic-eluting medical devices,including drug-eluting matrices and grafts); Zuckerman, Gels 6:9 (2020)(describing affinity-based release from cyclodextrin hydrogels);Richter, U.S. Pat. No. 7,048,714 (describing drug eluting medicaldevices having an expandable portion for drug release); Ding, U.S. Pat.No. 7,758,909, Lye, U.S. Patent Publication No. 2005/0070989, and Feng,U.S. Patent Publication No. 2008/0051881 (describing medical deviceshaving a porous surface/layer for controlled drug release); Fennimore,U.S. Pat. No. 8,007,737 (describing antioxidants for the prevention ofoxidation and degradation of drugs in drug-eluting medical devices);Atanasoska, U.S. Pat. No. 8,815,273 (describing drug-eluting medicaldevices having porous layers); Jennings, U.S. Pat. Nos. 9,605,175 and10,314,912 (describing polymer coating compositions for use in medicaldevices); Gemborys, U.S. Pat. Nos. 9,801,983 and 10,159,769 (describingmedical devices for delivering bioactives to a point of treatment);Speck, U.S. Patent Publication No. 2011/0295200, Zilberman, U.S. PatentPublication No. 2016/0082161, and Hoffmann, U.S. Patent Publication No.2011/0301697 (describing drug-eluting medical devices); Wong, PCT PatentPublication No. 2006/135609 (describing asymmetric drug-elutinghemodialysis grafts); Hanson, PCT Patent Publication No. 2008/156487 andPeck, PCT Patent Publication No. 2014/144188 (describing drug-elutinggrafts for the local drug delivery to tissues). Each of these scientificand medical articles, patents, and patent publications is incorporatedby reference herein in its entirety.

Drug-eluting matrices and grafts for use with the tissue repair andsealing devices disclosed herein may include one or more drugs ortherapeutic agents including, for example, anti-infectives,antineoplastics, biologicals, cardiovascular agents, central nervoussystem agents, coagulation modifiers, gastrointestinal agents,genitourinary tract agents, hormones, immunologic agents, and metabolicagents as are well known and readily available in the art.

2. Biocompatible Materials for Use in Tissue Repair and Sealing Devices

The tissue repair and sealing device of the present disclosure comprisesseveral biocompatible and/or bioresorbable elements configured to placea graft composed of natural or synthetic material on the inner surfaceof a tissue fenestration, at which time the graft is secured in place byrelease of a biodegradable clasp mechanism onto the outer surface of thetissue. Specifically, after passage of the graft through the tissue, andplacement to completely cover the inner edges of the defect, a slidingcylindrical release mechanism on the applicator releases flexiblebioresorbable clasps to deploy on the outer surface of the tissue,thereby securing the graft in place and providing an immediatewatertight repair and sealing of the defect. The graft-clasp unit isapplied using a detachable applicator shaft, which couples to thegraft-clasp unit during graft placement, and is subsequently detachedafter the graft is secured.

The coupling device and clasp are composed of flexible bioabsorbablematerial, which can be designed to apply the required tensile strengthof the radial struts to secure the graft in place, and to be completelyabsorbed over a period of time which allows healing of the graft to thetissue.

As used herein, the term “bioresorbable” refers to materials that arebroken down and absorbed by the body, and thus do not need to be removedmanually. Biosorbable materials include (1) metals or their alloys,commonly magnesium-based and iron-based alloys and (2) polymersincluding biopolymers, and copolymers thereof, such as polylactide(PLA), polyglycolide (PGA), polylactide-co-D, L lactide (PDLLA),polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL),polycaprolactone (PCL), polydioxanone (PDO), polylactide-co-trimethylenecarbonate (PL-TMC) which can be customized to meet mechanicalperformance parameters, biocompatibility, and resorption rates.

Bioresorbable materials may be processed via traditional manufacturingmethods including injection moulding, extrusion, compression mouldingand machining. These polymers may also be used in novel manufacturingmethods such as electrospinning, selective laser sintering, and fusiondeposition modeling.

Biopolymers are available that exhibit good biocompatibility and producedegradation products that are eliminated from the body by metabolicpathways. PLA-based substrates are non-toxic and permit cells todifferentiate to, for example, produce extracellular matrix components.

The mechanical properties of bioresorbable materials as well as theability to prolong the degradation time makes polylactide (PLA)poly(lactide-co-glycolide) (PLGA,) and poly(L-lactide-co-D, L lactide)(PDLLA) particularly advantageous material options. As with sutureanchors the addition of calcium phosphate helps promote bone growth,while absorbing at a slow enough rate to allow proper functionality ofthe implant. This controlled degradation is highly beneficial for thisapplication as the ingrowth of bone tissue into the interference screwregion allows for the native tissue fixation of the implanted tendon tooccur resulting in better patient outcomes once the bioresorbable screwis completely degraded.

Poly L-lactide-co-D, L lactide (PDLLA) have good tensile strength,excellent mechanical and thermal properties. Since most of theseapplications do not require the implant to be placed under an elevatedmechanical load, bioresorbable materials used for these treatments havefocused on enhancing the biological response and ability to promotehealthy bone regeneration without causing any adverse side effects upondegradation.

Poly dioxanone (PDO) polymers can be fabricated to provide materialshaving a desired degree of flexibility, good mechanical properties, anda fast to moderate degradation profile ranging from about 6 to about 12months. Poly dioxanone (PDO) polymers are suitable for use in themanufacture of grafts, clasps, and central couplers according to thepresent disclosure, which are able to secure regenerating tissue systemsin place long enough to allow for full healing after which the graftsand sutures degrade and become resorbed by the body. The degradationprofile of the depends on multiple factors such as polymercrystallinity, molecular weight, sterilisation method, and in vivoenvironment.

Biopolymers that may be advantageously employed in the tissue repair andsealing devices disclosed herein exhibit one or more of the mechanicalproperties that are presented in Table 1.

TABLE 1 Mechanical Properties of Biopolymers Mechanical Property LowerLimit Upper Limit Young's Modulus 1.75 GPa 2.04 GPa Specific Stiffness1.28 MN · m/kg 1.54 MN · m/kg Yield Strength (Elastic 42 MPa 55 MPaLimit) Tensile Strength 44.6 MPa 52.1 MPa Specific Strength 30.9 kN ·m/kg 41.1 kN · m/kg Elongation 3.89% Strain 5.6% Strain CompressiveModulus 1.75 GPa 2.04 GPa Compressive Strength 53.6 MPa 62.5 MPaFlexural Modulus 1.75 GPa 2.04 GPa Flexural Strength (Modulus 60.9 MPa79.8 MPa of Rupture) Shear Modulus 0.625 GPa 0.729 GPa Shear Strength2.92 MPa 3.4 MPa Bulk Modulus 2.93 Pa 3.41 Pa

Bioresorbable materials may be processed via traditional manufacturingmethods including injection moulding, extrusion, compression mouldingand machining. These polymers may also be used in novel manufacturingmethods such as electrospinning, selective laser sintering, and fusiondeposition modeling.

Biocompatible and bioresorbable materials have been described in the artthat may be adapted for use in the presently disclosed tissue repair andsealing devices. See, for example, AZoM, Biomaterials, 2630 (2004)(describing the classifications and physical characteristics ofbiomaterials for use in medical devices); Evonik, Medical Plastics News(describing applications for bioresorbable materials in medicaldevices); Gilding, Polymer 20(12):1459 (1979) (describing biodegradablepolymers, including polyglycolic acid (PGA) and polylactic acid (PLA)homo- and copolymers for use in medical devices, in particular insurgical devices); Kadam, Medical Plastics News 15:22 (2020) (discussingapplications for medical polymers for developing efficient medicaldevice technologies); Middleton, Biomaterials 21(23):2335 (2000)(discussing synthetic biodegradable polymers for use in orthopedicdevices); Santos, Tissue Engineering 225 (Ed. Daniel Eberli, 2010)(reviewing bioresorbable polymers for use in tissue engineering); andSheikh, Materials 8:5744 (2015) (reviewing biodegradable materials foruse in bone repair and tissue engineering). Each of these scientific andmedical articles is incorporated by reference herein in its entirety.

Within certain embodiments, the tissue repair and sealing devicesdisclosed herein may utilize a detachable graft and clasp assembly inwhich a graft subassembly and/or deployable clasp and couplersubassembly that incorporates a biocompatible, non-ferromagnetic,passivated metal or metal alloy in a graft 57, form ring 61, centralcoupler 67, and/or deployable clasp 75 to provide or enhance the shapememory and superelasticity characteristics of those component parts thethe tissue repair and sealing device.

Suitable biocompatible, non-ferromagnetic, passivated metal or metalalloys for use in the tissue repair and sealing devices disclosed hereininclude, but are not limited to, cobalt-based alloys, pure titanium,titanium-based alloys, platinum-based alloys, molybdenum, tungsten, andtantalum alloys. Suitable passivated metal or metal alloy wires for usein detachable graft and clasp assemblies exhibit desirable shape memoryand superelasticity characteristics such as those exhibited bynickel-titanium (Nitinol) and/or niobium-titanium.

Biocompatible, non-ferromagnetic, passivated metal or metal alloy havebeen described in the art that may be adapted for use in the presentlydisclosed tissue repair and sealing devices. See, for example, U.S. Pat.No. 8,349,249 (“Wachter”) and U.S. Pat. No. 8,992,761 (“Lin”), which areincorporated by reference herein.

Methods for the Use of Tissue Repair and Sealing Devices

The present disclosure provides methods for the use of tissue repair andsealing devices in both MIS and non-MIS procedures to achieve the rapidrepair of fenestrated tissues and the reliable creation ofpressure-resistant watertight seals. The tissue repair and sealingdevices disclosed herein comprise, in operable combination, (1) anapplicator assembly comprising a clasp retain and release member havinga proximal end and a distal end that is movably attached to anapplicator shaft having a proximal end and a distal end and (2) adetachable graft and clasp assembly comprising a graft subassembly and adeployable clasp and coupler subassembly that is fixedly attached to thecenter of the graft.

Thus, within certain embodiments, methods for the use of tissue repairand sealing devices disclosed herein comprise: (1) selecting adetachable graft and clasp assembly, as disclosed herein, (2) attachingthe detachable graft and clasp assembly to an applicator assemblycomprising an applicator shaft and a clasp retain and release member,(3) folding the clasp and inserting into the clasp retain and releasemember (4) positioning the graft on an inner tissue surface, (5)positioning the deployable clasp on an outer tissue surface, (6)securing the graft to the inner tissue surface by releasing thedeployable clasp onto the outer surface, (7) repairing a tissuefenestration, and (8) creating a pressure-resistant, watertight seal.

FIGS. 3B-3E illustrate a method for the use of a tissue repair andsealing device comprising graft subassembly and a deployable clasp andcoupler subassembly as illustrated in FIG. 1 and FIG. 2 to rapidlyrepair a tissue fenestration and create a pressure-resistant, watertightseal.

FIG. 3B illustrates steps in preparing an exemplary tissue repair andsealing device for use in repairing and sealing a tissue fenestration.Detachable graft and clasp assembly 50 is attached to applicatorassembly 20 at the proximal end 27 of applicator shaft 25 and the foldedradial struts or spokes 77 of deployable clasp and coupler subassembly65 are retained at the proximal end 37 of clasp retain and releasemember 35. Prior to insertion of a graft subassembly 57 through a tissuefenestration, the radial struts or spokes 77 of a deployable clasp andcoupler subassembly 65 are folded away from the graft subassembly 55 andalong a center of axis) that passes through central coupler 67 andinserted into the proximal end of the clasp retain and release member35.

The graft is brought close to the defect under direct, microscopic orendoscopic vision, to determine the optimal size and shape of the graftsubassembly 55 with relation to the size and shape of the fenestration.The central coupler 67 on the deployable clasp and coupler assembly 65allows the rapid exchange and selection of detachable graft and claspassemblies 55 by the surgeon to provide the optimal size, shape, andmaterial for the graft to seal the tissue fenestration.

In FIG. 3C is shown the tissue repair and sealing device of FIG. 3Bafter insertion of the graft subassembly 57 through the tissuefenestration such that it covers the entire opening on the inside of thedefect, then graft subassembly 57 is pulled back so that it contacts theinner surface of the fenestrated tissue while the deployable clasp andcoupler subassembly 65 remains outside of the fenestrated tissue priorto deploying the tissue repair and sealing device. Re-expansion of thegraft after passage through the fenestration may be facilitated by usinga flexible, semi-rigid graft material, or by incorporating a flexiblering of bioresorbable material around the circumference of the graft (asshown in FIGS. 6-8 and FIGS. 13C-13D). Thus, graft subassembly 55 isconfigured to easily deforms to fit through a tissue fenestration and tore-expand to its original shape upon entering the inside of the tissue.

In FIG. 3D is shown the deploying of the tissue repair and sealingdevice. Once graft subassembly 55 is positioned on the inner surface anddeployable clasp and coupler subassembly 65 is positioned on an outsidetissue surface, the device is deployed by sliding the clasp retain andrelease member 35 toward the distal end 29 of applicator shaft 25 to,thereby, release the deployable clasp struts or spokes 77, which snapback to their original configuration and apply pressure against theouter surface of the fenestrated tissue, thereby securing the graft inan optimal position to seal the fenestration.

In FIG. 3E is shown the separation of the detachable graft and claspassembly 50 from the applicator assembly 20 and the positioning of thedeployable clasp and coupler assembly 65 against an outer tissue surfaceto secure the graft subassembly 55 to the inner tissue surface and,thereby, to rapidly repair the tissue fenestration and reliably create apressure-resistant, watertight seal.

FIG. 5 illustrates an alternate embodiment of the tissue repair andsealing devices disclosed herein that is configured for sealinglarge-bore needle punctures (e.g., arterial puncture or lumbar puncture)or ostomies (surgical openings) into hollow body organs or cavities,usually associated with drainage of fluid through a needle or theplacement of a tube or cannula for infusion or drainage (e.g., lumbardrain, gastrostomy tube, thoracentesis drain, abdominal paracentesis,arterial catheter, suprapubic cystostomy) that is created for infusionor drainage tubes. In this embodiment, applicator shaft 25 is fabricatedout of a flexible material to enable the passage of the tissue repairand sealing device through an endoscope, or by a percutaneous routeusing a guide wire passed through an internal channel in the detachablegraft and clasp assembly 50 and applicator shaft 25.

FIGS. 5C-5G show an exemplary method by which a tissue repair andsealing device as shown in FIG. 5A and FIG. 5B is used to repair atissue fenestration, such as, for example, a large-bore needle puncturedefect, including a puncture of an arterial wall, dura, stomach, orpleura. In these tissues, a puncture, with or without placement of adrain or cannula through the needle, can lead to persistent leakagethrough the puncture site, causing significant morbidity (e.g., hematomaformation, cerebrospinal fluid leakage, peritonitis, or pneumothorax).As shown in FIGS. 5A and 5B, occluder graft 57 has a conical shape andis deformable such that it can pass along the guide wire through a smallpuncture in a tissue barrier and re-expand so that the base of thedeformable conical occluder graft 57 completely covers the puncture onthe inner surface of the tissue. The size of the occluder graft may beselected based upon the size of the defect to be sealed and may becomprised of a bioresorbable polymer, as described herein, and mayfurther comprise a drug eluting component to provide the delivery of adrug to the site of the tissue fenestration.

FIG. 5C illustrates a large-bore needle 121 that is positioned through atissue barrier 125 such as arterial wall, dura, stomach, or pleura, withthe tip located in the lumen or cavity 127 inside the tissue barrier. Aflexible guide wire 123 is then inserted into the lumen or cavitythrough large-bore needle 121. It will by understood that a guide wiremay be positioned with a tubing or cannula that has been placed by apercutaneous approach (e.g., an arterial catheter, a lumbar spinaldrain, a ventriculostomy, a pleurocentesis tube, a gastrostomy, or asuprapubic cystostomy). In an alternative aspect of this method, theguidewire may be passed through an indwelling catheter prior to itsremoval (not shown).

As shown in FIG. 5D, once guide 123 is inserted, large-bore needle 121is removed leaving guide wire 123 in place and traversing the tissuefenestration. FIG. 5E illustrates the positioning of a tissue repair andsealing device by inserting the external end of guide wire 123 into theopening at the tip of conical occluder graft 57 and passing guide wire123 through the central channel of conical occluder graft 57, centralcoupler 67, and flexible applicator shaft 25 of applicator assembly 20and exiting at the distal end 29 of flexible applicator shaft 25. Priorto passing the tissue repair and sealing device along guide wire 123,the plurality of radial spokes or struts 77 are folded away from conicaloccluder graft 57 and inserted into the proximal end 37 of clasp retainand release member 35.

The tissue repair and sealing device is advanced along the guidewire 123to the puncture site and the conical occluder graft 57 is passed throughthe puncture hole and positioned against the inner surface of thepunctured tissue and the tissue repair and sealing device is deployed bymoving the clasp retain and release member 35 toward the distal end 29of the applicator shaft 25 to release the deployable clasp and couplersubassembly 65 (FIG. 5F). The plurality of radial struts or spokes 77 ofdeployable clasp 75 are positioned against, and apply pressure to, theouter tissue surface to secure the conical occlude graft 57, repair thepuncture, and create a pressure-resistant, watertight seal. Theapplicator assembly 20 is detached from the detachable graft and claspassembly 50, which remains at the puncture site, and the applicatorassembly 20 is removed by sliding along the guidewire 123 after whichthe guidewire 123 is removed (FIG. 5G).

FIGS. 22A-22E illustrates a method for the use of a tissue repair andsealing device comprising a graft subassembly 55 and deployable claspand coupler subassembly 65 as illustrated in FIGS. 20A-20C and FIGS.21A-21C to rapidly repair a tissue fenestration and create apressure-resistant, watertight seal. These tissue repair and sealingdevices provide particular advantages in the repair of fenestratedtissues having a small tissue fenestration and/or that are friable innature. In this embodiment, graft subassembly 55 is configured toinclude a plurality biocompatible, non-ferromagnetic, passivated metalor metal alloy wires 64, which exhibit shape memory and superelasticitycharacteristics, emanating radially from the center of graft 57. Thus,graft subassembly 55 is configured to easily deform to fit within claspretain and release member 35 and to re-expand to its original shape uponentering the inside of the tissue and moving of clasp retain and releasemember 35.

FIG. 22A illustrates an exemplary tissue repair and sealing device priorto deploying. Detachable graft and clasp assembly 50 is attached toapplicator assembly 20 at the proximal end 27 of applicator shaft 25 andthe folded radial struts or spokes 77 of deployable clasp and couplersubassembly 65 are retained at the proximal end 37 of clasp retain andrelease member 35. Prior to insertion of graft subassembly 57 through atissue fenestration, the radial struts or spokes 77 of a deployableclasp and coupler subassembly 65 are folded away from the graftsubassembly 55 and along a center of axis that passes through centralcoupler 67 and inserted into the proximal end of the clasp retain andrelease member 35. In this embodiment is shown clasp retain and releasemember 35 that is elongated to accommodate graft subassembly 55,including graft 57 that comprises a plurality biocompatible,non-ferromagnetic, passivated metal or metal alloy wires 64 that emanateradially from the center of graft 57 and that is folded away fromcentral coupler 67 in an umbrella or parasol configuration andrestrained by clasp retain and release member 35.

The graft is brought close to the defect under direct, microscopic orendoscopic vision, to determine the optimal size and shape of the graftsubassembly 55 with relation to the size and shape of the fenestration.The central coupler 67 on the deployable clasp and coupler assembly 65allows the rapid exchange and selection of detachable graft and claspassemblies 55 by the surgeon to provide the optimal size, shape, andmaterial for the graft to seal the tissue fenestration.

In FIG. 22B is shown the tissue repair and sealing device of FIGS.20A-20C and FIGS. 21A-21C after passage of the proximal end of claspretain and release member 35 and graft subassembly 55 though the tissuefenestration. In FIG. 22C is shown the deploying of graft subassembly 55by moving clasp retain and release member 35 along applicator shaft 25toward its distal end and stopping when the proximal end of clasp retainand release member 35 reaches the outside of the fenestrated tissue atthe site of the central coupler 67. In FIG. 22C, graft subassembly 55 isthen pulled back so that graft 57 contacts the inner surface of thefenestrated tissue while the deployable clasp and coupler subassembly 65remains outside of the fenestrated tissue and within clasp retain andrelease member 35.

In FIG. 22D is shown the release deployable clasp and couplersubassembly 65 from clasp retain and release member 35 by sliding theclasp retain and release member 35 toward the distal end 29 ofapplicator shaft 25 to, thereby, release the deployable clasp struts orspokes 77, which snap back to their original configuration and applypressure against the outer surface of the fenestrated tissue, therebysecuring the graft in an optimal position to seal the fenestration.

In FIG. 22E is shown the separation of the detachable graft and claspassembly 50 from the applicator assembly 20 and the positioning of thedeployable clasp and coupler assembly 65 against an outer tissue surfaceto secure the graft subassembly 55 to the inner tissue surface and,thereby, to rapidly repair the tissue fenestration and reliably create apressure-resistant, watertight seal.

1. Methods for the Repair and Sealing of Fenestrations in the Dura Mater

Within certain embodiments, tissue repair and seal devices disclosedherein are configured for the repair and sealing of cerebrospinal fluidleaks due to fenestrations in the dura mater covering the brain andspine. Integrity of the dura is essential for containing cerebrospinalfluid within the central nervous system. Cerebrospinal fluid pressure ishigher than that of adjacent tissues or body spaces.

This pressure differential perpetuates leakage of cerebrospinal fluidthrough even small fenestrations, and inhibits their spontaneoushealing. Leakage of spinal fluid can lead to numerous complications,including wound infection, meningitis, cerebral herniation, intracranialbleeding, and headaches due to intracranial hypotension. Openings in thedura occur spontaneously (e.g., congenital defect, tumor, infection),purposefully (e.g. durotomy for craniotomy or spinal surgery, lumbarpuncture, etc.), or inadvertently (dural laceration in spinal orendoscopic sinus surgery, trauma, etc.). Because the cerebrospinal fluidis under pressure with continued outward egress of cerebrospinal fluidthrough an unrepaired fenestration, as above, onlay grafts or glues tendto be displaced away from the outer surface of the dura and healing ofthe fenestration is impaired. Thus, spontaneous healing of duralopenings not repaired at the initial surgery is poor, and subsequentmeasures to stop the cerebrospinal fluid leak frequently requirere-hospitalization, re-operation, and/or other procedures such asharvesting additional tissue grafts or lumbar drainage catheters.

Current methods to seal dural fenestrations include one or combinationsof several methods; direct suturing, placement of natural or syntheticgrafts, tissue sealants, adjunctive tissue grafts to buttress the onlaygraft repair, injection of epidural blood (“blood patch”) or lumbardrainage. There are several commercially available dural substitutes,including human cadaveric dura, bovine and/or porcine pericardium, andvarious synthetic matrix formulations. These are usually applied asonlay grafts, occasionally with suturing or glue. The frequency ofcerebrospinal fluid leaks due to incompletely sealed dural openingsranges considerably depending upon the nature of the procedure and thelocation, ranging from 1-2% in spinal surgery (higher for re-operations)to 10-15% for pituitary and certain posterior fossa operations. Thefuture development of MIS approaches to the brain and spine are limitedin large part by the difficulty in re-establishing integrity of thedura. A major limitation in the repair and sealing of planned orinadvertent dural openings for MIS procedures is the difficulty insuturing the dura. This is generally due to the inaccessibility forconventional suturing at the site of the durotomy and/or the friabilityof dura in certain locations. Also, the close proximity of criticalneural structures (nerve roots, cranial nerves, spinal cord, brain,blood vessels) makes suturing hazardous in many settings, as passage ofthe needle through the dura can inadvertently damage these structures.Another application of the invention described herein for dural closuremay be for open (non-MIS) procedures of the cranium and spine, wherein aplanned incision in the dura is made to expose the underlying neuralstructures during craniotomy or laminectomy procedures. Suture closureof the dural incision is generally employed, but is time-consuming andoften not watertight. Additionally, the device may utilize the fixedperpendicular orientation of the graft-clasp unit on the applicatorshaft or an adjustable coupling device to enable rotation of thegraft-clasp unit to facilitate visualization of the fenestration andnearby structures.

2. Methods for the Repair and Sealing of Spinal Dural Punctures

Within certain embodiments, tissue repair and seal devices disclosedherein are configured for the repair and sealing of spinal duralpuncture sites for lumbar punctures and spinal drains. Such puncturescan cause persistent leakage of cerebrospinal fluid into the adjacentperi-spinal tissue, causing intracranial hypotension manifest byincapacitating headaches. For example, the incidence of headache fromcerebrospinal fluid leak can be as high as 80% following dural puncturefor spinal anesthesia. Current methods for closure of dural punctureleaks include bed rest and or the use of an epidural blood patch.Percutaneous repair and sealing of spinal dural punctures using thetissue sealing device described herein is accomplished by passing thedevice with a flexible applicator shaft along a guide wire at the timeof spinal drain or spinal puncture needle removal. The device is passedalong the guide wire until the conical bioresorbable occluder graftpasses through the puncture opening into the intradural space. Theoccluder graft is pulled back so that the base covers the puncturefenestration on the inner surface, after which applicator is withdrawnalong the guide wire. The restraining cylinder withdraws with theapplicator, releasing the grasp struts, which deploy on the outer duralsurface of the puncture fenestration to secure the graft and provide animmediate watertight seal. Because the occlude graft is bioresorbable,it would not need to be removed.

3. Methods for the Repair and Sealing of Visceral Hollow OrganFenestrations

Within certain embodiments, tissue repair and seal devices disclosedherein are configured for the repair and sealing of fenestrations in thewall of visceral hollow organs, including but not limited to esophagus,stomach, small and large intestine, rectum, bladder, ureter, uterus andvagina. Such fenestrations occur both spontaneously (e.g. tumor,infection), purposefully (e.g. incision or biopsy of the organ duringsurgery), or inadvertently (laceration or puncture during surgery).Fenestrations in such hollow organ walls usually require repair toprevent intraperitoneal leakage of enteral contents or urine, or ingressof bacteria through uterus or vagina, which can lead to peritonitis orfistula formation. Rapid and watertight repair and sealing of suchorgans can be accomplished using the tissue repair and sealing devicedescribed herein at the time of the procedure, thus preventing leakageand subsequent infection or the need for re-operation. In any of thesesettings, the graft may consist of autologous, homologous, heterologous,or synthetic materials, either directly incorporated as an integratedgraft-clasp unit, or substituted at the time of surgery using thebioresorbable graft frame and holder apparatus. Additionally, in any ofthese settings the device may utilize the fixed perpendicularorientation of the graft-clasp unit on the applicator shaft or anadjustable coupling device to enable rotation of the graft-clasp unit tofacilitate visualization of the fenestration and nearby structures.

4. Methods for the Repair and Sealing of Punctures, Perforations orOstomies

Within certain embodiments, tissue repair and seal devices disclosedherein are configured for the repair and sealing of punctures,perforations or ostomies in abdominal hollow organs after biopsy orremoval of a tube or cannula. Examples of the biopsy-related usesinclude perforations of esophagus, stomach, small or large intestine, orrectum occurring during trans-oral or trans-anal endoscopic biopsies, orperforations of the vagina and uterus, or bladder and ureters duringtrans-vaginal and trans-urethral endoscopic procedures, respectively. Inanother related embodiment, the tissue repair and sealing describeddevice herein may be used for the percutaneous repair of an ostomy orneedle puncture in a hollow organ wall, after removal of a drainagetube. This embodiment uses the flexible repair and sealing deviceadvanced through and endoscope or over a guide wire, and may be used forexternal percutaneous tubes, drains, or cannulas removed from theesophagus, stomach, small or large intestine, rectum, or bladder(suprapubic tube). The graft component in these applications may includeeither flat grafts of natural or synthetic material, or conical occludergrafts. As above, the benefit of immediate sealing of the tube ostomy isthe prevention of leakage of internal fluids into the peritoneum orthrough the skin via the percutaneous tube tract.

5. Methods for the Repair and Sealing of Body Cavity Fenestrations

Within certain embodiments, tissue repair and seal devices disclosedherein are configured for the repair and sealing of fenestrations ofbody cavities, including but not limited to peritoneum, pleural cavity,inner ear or joint space. Drainage of the pleural cavity viathoracentesis can be complicated by pneumothorax, caused by ingress ofair through the puncture site in the pleura. Similarly, percutaneous orendoscopic punctures of the peritoneum for surgical access or abdominalparacentesis (e.g. for drainage or dialysis) may subsequently leak alongthrough the cutaneous incision. Similarly, surgical procedures of theear or joints may create fenestrations in the tympanic membrane orsynovium, respectively. In these situations, the tissue repair andsealing device described herein, in either the rigid or flexible formwith flat or conical graft, can immediately seal the puncture site andprevent subsequent complications. Additionally, the device may utilizethe fixed perpendicular orientation of the graft-clasp unit on theapplicator shaft or an adjustable coupling device to enable rotation ofthe graft-clasp unit to facilitate visualization of the fenestration andnearby structures.

6. Methods for the Repair and Sealing Defects in Body Facia

Within certain embodiments, tissue repair and seal devices disclosedherein are configured for the repair and sealing of fenestrations ofdefects in body fascia, including but not limited to abdominal wall,chest wall or muscle and ligament fascia. Defects in these fascialstructures can lead to herniation of underlying tissues or woundbreakdown. Repair of body fascia using the device described herein mayinclude direct closure of the fascia in open (non-MIS) procedures usingsingle or multiple graft-clamp components applied to the fascial edges,or in the case of a large defect, the incorporation of a free graft ofnatural or synthetic material, which is secured circumferentially to thedefect edges using multiple graft-clasp units. In addition, the flexibleor rigid tissue repair and sealing device may be used to closefenestrations in fascia via endoscope or by percutaneous approach. Inany of these settings the device may utilize the fixed perpendicularorientation of the graft-clasp unit on the applicator shaft or anadjustable coupling device to enable rotation of the graft-clasp unit tofacilitate visualization of the fenestration and nearby structures.

7. Methods for the Localized Delivery of Drugs and Other Agents

Within certain embodiments, tissue repair and seal devices disclosedherein are configured for the continuous, localized delivery of drugsand other agents from a drug-eluting matrix incorporated into, orreplacing the graft component. Localized delivery of drugs providesseveral benefits; (a) the concentration of the drug is highest at thesite of application, and untoward effects from systemic distribution ofthe drug are minimized; (b) the drug can be administered in adequateconcentration to body compartments that are relatively inaccessible tothe drug administered by intravenous or oral route (e.g. cerebrospinalfluid due to blood-brain barrier restriction, poorly perfusedcompartments such as abscess cavity); (c) continuous delivery ensures atherapeutic steady-state concentration of the drug without the peak andtrough fluctuations which occur with intermittent administration; (d)patient compliance is not an issue; and (e) the drug-eluting matrix canbe biodegradable and engineered to release a specific drug at a knownrate and duration depending on the site of delivery. Many drug-elutingmatrices are currently in clinical use, although most involveimplantation of the matrix into subcutaneous or solid tissues. In thecurrent embodiment, any category of drug or bioactive agent could beimplanted and secured at any site in the body using the modified tissuerepair and sealing device, depending upon the clinical setting andintended therapeutic effect.

The distribution of the drug would depend upon the site of applicationof the matrix. For example, a matrix placed on the inner surface of ablood vessel could provide systemic distribution for a venous implantsite, or provide regional drug distribution to the downstream tissuesperfused by an artery (e.g. a neoplasm or single organ). Additionally, amatrix placed on the inner surface of a tissue barrier could providedrug delivery to the fluid or cavity enclosed by the barrier (e.g. duralimplant releasing drug into cerebrospinal fluid, peritoneal implantreleasing drug into peritoneal cavity, or gastrointestinal implantreleasing drug into the bowel). Also, the matrix placed on the inside ofa barrier could release drugs to modulate the barrier itself (e.g.promoting healing, inhibiting scarring or hyperplasia, or local paincontrol). Finally, a matrix implant placed inside the capsule of a solidorgan or tumor, in contact with the parenchyma, could provide local drugdelivery to that part of the organ or tumor (e.g. kidney, pituitary,malignant or benign tumor). As above, this application of the repair andsealing device could be applied to nearly every category of drugs andevery body organ and tissue type.

While various embodiments have been disclosed herein, other embodimentswill be apparent to those skilled in the art. The various embodimentsdisclosed herein are for purposes of illustration and are not intendedto be limiting, with the true scope and spirit being indicated by theclaims. The present disclosure is further described with reference tothe following examples, which are provided to illustrate certainembodiments and are not intended to limit the scope of the presentdisclosure or the subject matter claimed.

EXAMPLES Example 1

In Vitro Models for Testing Tissue Repair and Sealing Devices

This Example provides in vitro model systems that may be adapted andemployed for the testing various aspects of the tissue repair andsealing devices disclosed herein. Various physical properties and otherparameters of tissue repair and sealing devices as disclosed herein maybe tested in in vitro model systems, including in vitro model systemsthat are described in the scientific, medical, and patent literature andthat may be configured for testing the repair and sealing of tissuefenestrations with the devices disclosed herein. See, Dafford, The SpineJournal 15(5):1099 (2015); Chauvet, Acta Neurochirurgica 153(12):2465(2011); and Wang, MATEC Web of Conferences 119:01044 (2017).

Van Doormat, Operative Neurosurgery 15(4):425 (2018) and Kinaci, ExpertReview of Medical Devices 16(7):549 (2019) disclose in vitro modelsystems that use fresh porcine dura for testing acute burst pressuresand resistance to intracranial pressure and assessing cerebrospinalfluid leakage in repaired and sealed tissue fenestrations.

Megyesi, Neurosurgery 55(4):950 (2004); Chauvet, Acta Neurochir (Wien)153(12):2465 (2011); and Kizmazoglu, Br. J. Neurosurgery 33(6):655(2019) disclose in vitro model systems that use human cadaveric duramater attached to a cylindrical metal glass filled with colored salinefor measuring the water-tightness of repaired and sealed tissuefenestrations and for assessing the pressure at which a repaired andsealed tissue fenestration leaks.

Lin, International Forum of Allergy and Rhinology 6(10):1034 (2016);Lin, International Forum of Allergy and Rhinology 5(7):633 (2015);Chorath, Allergy & Rhinology 10:1 (2019); and Chen, American Journal ofRhinology and Allergy 33(6):757 (2019) disclose a porcine dura in vitromodel system using a closed testing apparatus that utilized an infusedsaline solution to provide unidirectional pressure for determining meanfailure pressures of repaired and sealed tissue fenestrations. The invitro model system employs polyvinyl chloride (PVC) piping capped at oneend. A small hole is drilled on the side of the end cap and configuredwith a 3-way stop cock to infuse saline solution and monitor chamberpressure, simulating increasing intracranial pressure (ICP). A siliconebrain is positioned under a simulated cribriform plate within acylindrical tube. A section of the cribriform plate with a 30 mm-25 mmopening is modeled according to a real computed tomography scan of theskull base (Able, Lexington, Mass.), imported into CAD (computer-aideddesign) software (3D Systems, Rockhill, S.C.), and printed inpolycarbonate (Airwolf, Costa Mesa, Calif.). A second dural support diskis prepared with an identical opening and positioned flushed to theopening of the simulated cribriform plate resection. The cavity pressurewas monitored with a pressure transducer (AMTEK, Inc., Ajman, UAE), andits output was transcribed directly onto an excel spreadsheet usingWindaqXL (DATAQ, Akron, Ohio). The transducer was calibrated in mm Hg,and all measurements were converted to centimeters of water (cm H2O).Porcine dura is used because of its similar mechanical properties tohuman dura. Porcine dura mater and fascia lata were harvested fromeuthanized pigs and placed in saline and stored at 4° C. Experimentationis conducted within 5 days of retrieval to avoid degradation of thedura. Dural defects are uniformly cut to 24 mm-19 mm dimensions.

Pressure chambers are designed to be adjustable to meet the demands ofvarious testing procedures. The body is made of a schedule 80 PVC Teefitting that has been outfitted with two flanges and an end cap. On theleft side, the end cap is drilled and tapped for a push connect tubefitting that will act as the influent port for our test fluid. Thisfluid flow is run through a three-way valve with one port controlled bya solenoid valve and the other by a syringe allowing for two differentmethods of controlling fluid flow. On the right side of the tee there isa flange upon which a membrane is fastened by a piece of acrylic. Thisacrylic has been designed to mount a 6.5″ speaker that will allow fortesting of pressure changes created by sound waves that mimic the body'snatural respiratory cycle and other human functions. On the top of thetee there is another flange which will hold the test bed. The test bedconsists of two pieces of acrylic that will sandwich a piece ofcommercially-available synthetic Dural material. On the underside of thelower acrylic plate is the pressure transmitter which will monitor thechanges in pressure for testing while also controlling, the solenoidvalve.

The pressure chamber used for testing graft subassemblies of the presentdisclosure is shown in FIG. 23A and FIG. 23B. FIG. 23C is a human CSFpressure waveform and FIG. 23D is an in vitro chamber pressure waveformobtained with the pressure chamber shown in FIG. 23A. For testing, aclosure device includes a probe that is controlled and operated singlehandedly. This device delivers a bioabsorbable base membrane beneath anincision. Upon insertion, a pressure web is applied on the outsidecreating a watertight seal. Once the placement is satisfactory, thedelivery probe is removed. Should the placement need adjustment it iscritical that the sealant device can be adjusted or removed.

Pressure variance via an external speaker that creates waveforms similarto those created naturally by the body, including the natural rhythms ofCSF flow, patient movements, coughing and sneezing. The seal is createdby the overlap of the dura and the base material. Key physical forcesrelied on for a watertight seal are the backpressure of CSF, uniformload from the tension arms, and the coefficient of friction between thetwo surfaces. Back pressure of CSF varies constantly depending on thepatient's body and movements. The load applied on the dura varies withthe size of each device due to material properties of PLGA. Thecoefficient of friction helps hold the device in place. A leak thatoccurs due to any of these forces is overcome in testing.

Example 2 In Vivo Models for Testing Tissue Repair and Sealing Devices

This Example provides in vivo model systems that may be adapted andemployed for the testing various aspects of the tissue repair andsealing devices disclosed herein. Various physical properties and otherparameters of tissue repair and sealing devices as disclosed herein maybe tested in in vivo model systems, including in vivo model systems thatare described in the scientific, medical, and patent literature and thatmay be configured for testing the repair and sealing of tissuefenestrations with the devices disclosed herein.

de Almeida, Otolaryngology Head Neck Surgery 141(2):184 (2009) and Seo,Journal of Clinical Neuroscience 58:187 (2018) describe in vivo porcinecraniotomy model system that may be adapted for testing the repair oftissue fenestrations by assessing the leakage of cerebrospinal fluids(CSF). In de Almeida, pigs undergo a craniotomy to create fistulathrough the cribriform plate into the nasal cavity. CSF leaks may beassessed endoscopically prior to and following the repair of tissuefenestration. Inflammation and bone remodeling may be assessed viahistopathological analysis.

Dafford, Spine Journal 15(5):1099 (2015) describes a comparison of thehydrostatic strength of dural repair techniques in a hydrostatic calfspine model system. Dural leakage is measured as a function ofhydrostatic pressure and leak area. Leakage flow rate and the percentreduction of leak area is determined using analysis of variance (ANOVA).

Deng, Neurological Research 38(9):799 (2016); Preul, Neurosurgery53(5):1189 (2003); and Zerris, Journal of Biomedical Materials Research83(2):580 (2007) describe in vivo canine cranial dura and arachnoidmodel systems for assessing CSF leakage. Deng also reports macroscopicand microscopic observations at 30 and 90 days following dura repair.Preul reports the results of Valsalva tests at 1, 4, 7, and 56 dayspost-surgery and of histopathological analyses for control and treatedanimals.

Cosgrove, Journal of Neurosurgery 106:52 (2007); Osbun, WorldNeurosurgery 78(5):498 (2012); and Weinstein, Journal of Neurosurgery112(2):219 (2010) describe in vivo craniotomy and craniectomymethodology that may be adapted for testing the repair of tissuefenestrations by assessing the leakage of CSF in humans. Theneurological procedures used in Cosgrove are performed infratentoriallyor supratentorially using suboccipital, temporal, and frontal surgicalapproaches with durotomy lengths ranging from 1.0-19.0 cm. Osbunassesses complications resulting in unplanned postoperativeinterventions or reoperations following dural closure and compares theincidence of surgical site infections, CSF leaks, and other neurologicalcomplications in both treatment (dural repair) and control groups.

The scope of the disclosure is thus indicated by the appended claimsrather than by the foregoing, description, and all changes that comewithin meaning, and range of equivalency of the claims are intended tobe embraced herein.

What is claimed is:
 1. A tissue repair and sealing device for use in anopen (non-MIS) or minimally invasive surgical (MIS) procedure forrapidly repairing a tissue fenestration and creating apressure-resistant, watertight seal, said device comprising: a. anapplicator assembly comprising an applicator shaft having a proximal endand a distal end and a clasp retain and release member having a proximalend and a distal end, wherein said clasp retain and release member ismovably connected to said applicator shaft and b. a detachable graft andclasp assembly comprising, in operable combination, a graft subassemblycomprising a graft fixedly attached to a deployable clasp and couplersubassembly comprising a deployable clasp and central coupler; i.wherein said detachable graft and clasp assembly is configured forpositioning the graft on an inner tissue surface and positioning thedeployable clasp on an outer tissue surface and ii. wherein saiddetachable graft and clasp assembly attaches via the central coupler tothe applicator assembly at the proximal end of the applicator shaft. 2.The tissue repair and sealing device of claim 1 wherein said deployableclasp assembly is configured to adopt a folded configuration whenretained by said clasp retain and release member and to rapidly unfoldto a pre-folded state.
 3. The tissue repair and sealing device of claim1 wherein said device is deployed by moving said clasp retain andrelease member toward the distal end of said applicator shaft to,thereby, release said folded deployable clasp, wherein upon deployingsaid device the deployable clasp unfolds and contacts an outer tissuesurface to secure said graft to an inner tissue surface and, thereby,repair a tissue fenestration and creates a pressure-resistant,watertight seal.
 4. The tissue repair and sealing device of claim 1wherein said deployable clasp comprises a biopolymer selected from thegroup consisting of a polylactide (PLA), a polyglycolide (PGA), apolylactide-co-D, L lactide (PDLLA), a polylactide-co-glycolide (PLGA),a polylactide-co-caprolactone (PLCL), a polycaprolactone (PCL), apolydioxanone (PDO), and a polylactide-co-trimethylene carbonate(PL-TMC), wherein said biopolymer exhibits shape memory andsuperelasticity characteristics that permit the folding of saidbiopolymer while retaining the capacity to rapidly unfold to apre-folded state.
 5. The tissue repair and sealing device of claim 1wherein said deployable clasp assembly comprises a biocompatible,non-ferromagnetic, passivated metal or metal alloy wire that is selectedfrom the group consisting of pure titanium; a titanium-based alloy; acobalt-based alloy; a platinum-based alloy; and a molybdenum, tungsten,and tantalum alloy. wherein said biocompatible, non-ferromagnetic,passivated metal or metal alloy wire exhibits shape memory andsuperelasticity characteristics that permit the folding of said wirewhile retaining the capacity to rapidly unfold to a pre-folded state. 6.The tissue repair and sealing device of claim 5 wherein saidbiocompatible, non-ferromagnetic, passivated metal or metal alloy isselected from the group consisting of a nickel-titanium alloy (Nitinol)and a niobium-titanium alloy.
 7. The tissue repair and sealing device ofclaim 1 wherein said graft assembly is configured (a) to adopt a foldedconfiguration when traversing a tissue fenestration or when retained bysaid clasp retain and release member and (b) to rapidly unfold to apre-folded state.
 8. The tissue repair and sealing device of claim 1wherein said graft is selected from the group consisting of anautograft, an isograft, an allograft, and a xenograft and wherein saidgraft is derived from an animal tissue is selected from the groupconsisting a human tissue, a bovine tissue, and a porcine tissue.
 9. Thetissue repair and sealing device of claim 1 wherein said graft materialcomprises one or more synthetic material selected from the groupconsisting of poly(ethylene terephthalate) and expandedpolytetrafluoroethylene (ePTF).
 10. The tissue repair and sealing deviceof claim 1 wherein said graft comprises an acellular, porousextracellular matrix scaffold of collagen, elastin, and, optionally, agrowth factor.
 11. The tissue repair and sealing device of claim 1wherein said graft comprises a dural substitute selected from the groupconsisting of Duraform® dural graft implant, Biodesign® Dural Graft,DuraGen® Matrix, Cerafix dural Graft®, PRECLUDE®, Lyoplant Onlay Graft®,Neuro-Patch Dural Graft®, SEAMDURA®, and Durepair™ Regeneration Matrix.12. The tissue repair and sealing device of claim 1 wherein said graftcomprises a drug eluting matrix.
 13. The tissue repair and sealingdevice of claim 1 wherein said graft comprises a biocompatible,non-ferromagnetic, passivated metal or metal alloy wire that is selectedfrom the group consisting of pure titanium; a titanium-based alloy; acobalt-based alloy; a platinum-based alloy; and a molybdenum, tungsten,and tantalum alloy. wherein said biocompatible, non-ferromagnetic,passivated metal or metal alloy wire exhibits shape memory andsuperelasticity characteristics that permit the folding of said wirewhile retaining the capacity to rapidly unfold to a pre-folded state.14. The tissue repair and sealing device of claim 13 wherein saidbiocompatible, non-ferromagnetic, passivated metal or metal alloy isselected from the group consisting of a nickel-titanium alloy (Nitinol)and a niobium-titanium alloy.
 15. A method for the use of a tissuerepair and sealing device in an open (non-MIS) or minimally invasivesurgical (MIS) procedure to rapidly repair a tissue fenestration andcreate a pressure-resistant, watertight seal, comprising: (a) selectinga tissue repair and sealing device having a detachable graft and claspassembly removably attached to an applicator assembly, wherein saiddetachable graft and clasp assembly comprises a graft subassembly havinga graft that is fixedly attached to a deployable clasp and couplersubassembly having a deployable clasp with radial struts or spokes and acentral coupler and wherein said applicator assembly comprises anapplicator shaft, a clasp retain and release member, and an actuatorrod; (b) folding the deployable clasp radial struts or spokes and andinserting into the clasp retain and release member; (c) inserting thegraft through a tissue fenestration and positioning the graft on aninner tissue surface; (d) positioning the deployable clasp and couplersubassembly on an outer tissue surface; (e) deploying the tissue repairand sealing device to release the deployable clasp from the clasp retainand release member to contact the outer tissue surface and secure thegraft to the inner tissue surface, repairing the tissue fenestration,and create a pressure-resistant, watertight seal.
 16. The method ofclaim 15 wherein said device is deployed by moving said clasp retain andrelease member toward the distal end of said applicator shaft to,thereby, release said folded deployable clasp, wherein upon deployingsaid device the deployable clasp unfolds and contacts an outer tissuesurface to secure said graft to an inner tissue surface and, thereby,repair a tissue fenestration and creates a pressure-resistant,watertight seal.
 17. The method of claim 15 wherein said deployableclasp comprises a biopolymer selected from the group consisting of apolylactide (PLA), a polyglycolide (PGA), a polylactide-co-D, L lactide(PDLLA), a polylactide-co-glycolide (PLGA), apolylactide-co-caprolactone (PLCL), a polycaprolactone (PCL), apolydioxanone (PDO), and a polylactide-co-trimethylene carbonate(PL-TMC), wherein said biopolymer exhibits shape memory andsuperelasticity characteristics that permit the folding of saidbiopolymer while retaining the capacity to rapidly unfold to apre-folded state.
 18. The method of claim 15 wherein said deployableclasp assembly comprises a biocompatible, non-ferromagnetic, passivatedmetal or metal alloy wire that is selected from the group consisting ofpure titanium; a titanium-based alloy; a cobalt-based alloy; aplatinum-based alloy; and a molybdenum, tungsten, and tantalum alloy.wherein said biocompatible, non-ferromagnetic, passivated metal or metalalloy wire exhibits shape memory and superelasticity characteristicsthat permit the folding of said wire while retaining the capacity torapidly unfold to a pre-folded state.
 19. The method of claim 15 whereinsaid graft assembly is configured (a) to adopt a folded configurationwhen traversing a tissue fenestration or when retained by said claspretain and release member and (b) to rapidly unfold to a pre-foldedstate.
 20. The method of claim 15 wherein said graft comprises a duralsubstitute selected from the group consisting of Duraform® dural graftimplant, Biodesign® Dural Graft, DuraGen® Matrix, Cerafix dural Graft®,PRECLUDE®, Lyoplant Onlay Graft®, Neuro-Patch Dural Graft®, SEAMDURA®,and Durepair™ Regeneration Matrix.